TWI221406B

TWI221406B - Systems and methods for targeted magnetic resonance imaging of the vascular system

Info

Publication number: TWI221406B
Application number: TW091116939A
Authority: TW
Inventors: Robert M Weisskoff; Peter D Caravan; Sonia Witte; Randall B Lauffer; Alan P Carpenter Jr
Original assignee: Epix Medical Inc
Priority date: 2001-07-30
Filing date: 2002-07-29
Publication date: 2004-10-01
Also published as: CA2455210A1; HUP0401548A2; AU2002322789C1; HUP0401548A3; JP2008220966A; PL366736A1; WO2003011113A3; JP2006006962A; AU2002322789B2; EP1420689A2; US20030028101A1; BR0211607A; EP1420689A4; JP2004536649A; KR20040018529A; ZA200401605B; MXPA04000955A; US7412279B2; WO2003011113A2; CN1635855A

Abstract

This invention relates to MRI-based methods and systems useful for diagnosing and clinically assessing the presence, location, and size of cardiovascular disease-associated stationary targets, e.g., thrombi and atherosclerotic lesions, within the vascular system. Methods and systems of the invention allow for improved anatomical information to be obtained from MRI images and allow the clinician to develop more effective treatment plans. In one aspect, the invention provides a method of determining the presence or absence of a stationary target within the vascular system of a mammal wherein two MRI data sets representing images of the vascular system and the stationary target are acquired after administration of a targeted MRI contrast agent. In another embodiment, both a targeted MRI contrast agent and a vascular MRI contrast agent are administered to a mammal, and both a vascular MRI and a targeted MRI data set are acquired.

Description

1221406 A7 B7 五、發明説明（1 ) 相關申請案資料本申請案根據35 U.S.A· § 119(e)(1)主張2001年7月30曰申請之美國臨床專利申請案第60/308,690號之優先權，其標題為”血管組織標靶磁共振顯影之系統及方法”。技術領域本案是有關血管系統及心血管疾病系狀況之磁振顯影，且特別的有關固定標靶，如在血管系内之血栓或動脈粥樣硬化傷害，經改進之偵測，定位及臨床評估之系統及方法〇背景心血管疾病（CVDs)，如高血壓，心臟病發，中風，心絞痛’動脈粥樣硬化，及動脈硬化，侵犯數百萬人且是現今世界主要死亡原因。CVDs主要由逐漸變窄的動脈所組成，而其係助長器官或組織，如心臟。變窄的原因是脂肪斑沿著動脈壁過度堆積。斑之組成造成動脈瘤及血栓，即血液凝塊’接著血栓造成血栓症，心臟病發及中風。 CVD治療的關鍵是早期偵測及診斷，如此才可開始適切的治療。在血管系統内正確鑑定CVD之存在，所在及大小’如血栓或動脈粥樣硬化傷害，對於發展正確的治療過程’手術介入之必要，及手術或治療之位置，在診斷上極具意義。斑構成，動脈瘤，血栓，及其他傷害或疾病過程之有效偵測及診斷，常需使用顯影技術以具象化病人的血管系統。此顯影技術包括X-射線血管攝影，電腦斷層攝影（CT) -5- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)1221406 A7 B7 V. Description of the invention (1) Related application materials This application claims the priority of US Clinical Patent Application No. 60 / 308,690 filed on July 30, 2001 based on 35 USA · § 119 (e) (1) The title is "System and Method for Magnetic Resonance Imaging of Vascular Tissue Targets". TECHNICAL FIELD This case relates to magnetic resonance imaging of conditions of the vascular system and cardiovascular disease system, and specifically relates to fixed targets, such as thrombus or atherosclerotic injury in the vascular system, with improved detection, location and clinical evaluation. SYSTEMS AND METHODS Background: Cardiovascular diseases (CVDs), such as hypertension, heart attacks, strokes, angina pectoris' atherosclerosis, and arteriosclerosis, invade millions and are the leading cause of death in the world today. CVDs are mainly composed of narrowing arteries, and they promote organs or tissues, such as the heart. The narrowing is caused by excessive accumulation of fatty plaque along the arterial wall. The composition of the plaque causes an aneurysm and a thrombus, that is, a blood clot 'followed by a thrombus causes thrombosis, a heart attack, and a stroke. The key to CVD treatment is early detection and diagnosis so that appropriate treatment can begin. The correct identification of the presence of CVD in the vascular system, such as the presence of thrombus or atherosclerotic injury, is necessary for the development of the correct treatment process, and the location of the operation or treatment is of great diagnostic significance. The effective detection and diagnosis of plaque formation, aneurysms, thrombi, and other injury or disease processes often requires the use of imaging techniques to visualize the patient's vascular system. This development technology includes X-ray angiography, computer tomography (CT) -5- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

裝 f 1221406 A7 ___ Β7_ 五、發明説明（2 ) 及螺旋CT血管攝影，及磁振造影（MRI)。使用磁振血管攝影（MRA)診斷CVDs已漸受歡迎，因為其大抵上已知在花費上是有效率，合宜且安全的。MRA是一種非侵入性MRI技術’其中使用知·的磁脈衝對供應血液至心臟及其他重要器官之動脈及血管可提供三度空間（"3D")造影。在MRA檢查中可投予對比劑，以改善血管系之具象化。對比劑是一種物質，其當投予至個體，可增加所選定標把’組織’或器官及造影其他範圍間（如其餘身體區域）之造影對比（如提供加強之對比）。”血管”對比劑經由改變血管系相較於周圍組織之對比，可改善血管系之具象化，通常經由加亮（過度強化）血管系（如血液）而成。將血管對比劑注入病人的血流内可提供血管系造影對比之加強’且使主治醫師可具象化及偵測血管之直徑，包括極小者。正確地明定出血管尺寸及直徑對於Cvd診斷是十分重要的，因為血管直徑可顯示狹窄之存在，特徵在於血管變窄’及動脈瘤，特徵在於血管之加寬。在Mri檢查中使用血管對比劑，也可間接地偵測其他型式之CVDs ^例如’血栓及動脈粥樣硬化傷害因其會取代血液因而可被間接偵測，造成血管在對比加強之造影中有被阻斷或窄化狀估不論血管對比劑之使用，血管系中CVDs之診斷仍十分困難。例如，醫師必須在亮的（如加強的）血管系内尋求暗的區域（如負面對比區域）^此外，使用血管對比劑通常醫師仍無法區別在血管内含有血栓之血管及某些其他阻斷型 -6- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Equipment f 1221406 A7 ___ Β7_ 5. Description of the invention (2) and spiral CT angiography, and magnetic resonance imaging (MRI). The use of magnetic resonance angiography (MRA) for the diagnosis of CVDs has become increasingly popular because it is generally known to be cost effective, affordable, and safe. MRA is a non-invasive MRI technique, in which known magnetic pulses are used to provide three-dimensional (" 3D ") imaging of arteries and blood vessels that supply blood to the heart and other important organs. Contrast agents can be administered during MRA to improve the visualization of the vascular system. A contrast agent is a substance that, when administered to an individual, can increase contrast contrast (eg, provide enhanced contrast) between a selected target 'tissue' or organ and other areas of the contrast (eg, the rest of the body area). "Vascular" contrast agents can improve the visualization of the vascular system by changing the contrast of the vascular system compared to surrounding tissues. It is usually made by highlighting (over-strengthening) the vascular system (such as blood). Injecting a vascular contrast agent into a patient's blood stream can provide enhanced angiographic contrast 'and allow the attending physician to visualize and detect the diameter of the blood vessels, including those that are extremely small. Correctly clarifying the size and diameter of blood vessels is very important for Cvd diagnosis, because the diameter of blood vessels can show the existence of stenosis, which is characterized by narrowing of blood vessels' and aneurysms, which are characterized by widening of blood vessels. The use of vascular contrast agents in Mri examination can also indirectly detect other types of CVDs ^ For example, 'thrombosis and atherosclerotic injury can replace blood and can be detected indirectly, resulting in blood vessels in contrast-enhanced angiography. Estimation of blocked or narrowed conditions Regardless of the use of vascular contrast agents, the diagnosis of CVDs in the vascular system is still very difficult. For example, physicians must look for dark areas (such as negative contrast areas) in bright (eg, strengthened) blood vessels. ^ Furthermore, with vascular contrast agents, physicians often cannot distinguish between blood vessels that contain blood clots in blood vessels and certain other blockages. Type-6- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

裝 t A7 --~-----B7 五、發明説明（3 )" "------ 式間之區域（如在血管壁内之阻斷）。姓另一型式之對比劑，在此稱為”標靶的"對比劑，作用係結合至特殊的標乾，其可能存在於血管系統内。例如，標乾的作用物可與血管内之CVD標乾結合，如血栓。因此，經由高度強化相較於背景組織及血液之標靶，標靶作用物 I可加強標靶及背景組織及血液間之對比。然而，使用此標乾作用物並播法示出對比加強之標起確實是在血管内，也 2 =鑑定血管系内標乾本身之所在或尺寸。因此，標乾造〜$缺乏CVDs有效診斷及治療所必需之重要解剖學資料。利用費用-有效率，安全且合宜的方法，對於醫師可正確地鑑定血管系内CVD標靶之存在，所在及大小將是十分有用的。對於醫師可區別所選定之標靶（如CVD)及血管系互相之間，以及區別視野内其餘的背景組織，也進一步十分有用的。發明要點本發明疋有關以MRI -為基礎之方法及系統，可用於診斷及臨床評估血管内CVDs，如血栓及動脈粥樣硬化傷害，之存在’所在及大小。使用本發明方法及系統，可由血管及標乾MRI造影中取得關於cVDs改進的解剖資訊，且使此研究更具彈性，有助病人正確之處置。因此，在本發明的一方面是提出決定哺乳動物血管系内固定標乾存在與否之方法。血管系内固定標乾可為如··組織’生物結構’細胞’細胞表面及生物聚合物^生物結構之實例包括CVDs ’如血栓，動脈粥樣硬化斑，動脈粥樣硬本纸杀尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1221406 A7 _ B7 五、發明説明（~~~" 一化傷害，腫瘤及血栓插栓。.另外，固定標把可為生物聚合物。生物聚合物之實例包括脂質，脂蛋白，蛋白質，多肽’及多_。若生物聚合物是蛋白質，其可為以較高濃度存在於CVDs之蛋白質，包括血纖維蛋白及膠原蛋白。Installation t A7-~ ----- B7 V. Description of the invention (3) " " ------ The area between the patterns (such as the block in the vessel wall). Another type of contrast agent, referred to herein as a "target" contrast agent, binds to a special target, which may be present in the vascular system. For example, the target of the standard can be related to the target in the blood vessel. CVD target binding, such as thrombus. Therefore, Target Agent I can enhance the contrast between the target and background tissue and blood through highly enhanced compared to the target of background tissue and blood. However, using this target The simulative method shows that the contrast-enhanced mark is indeed in the blood vessel, and also 2 = identify the location or size of the standard stem itself in the vascular system. Therefore, the standard stem lacks the important anatomy necessary for effective diagnosis and treatment of CVDs. Information. The use of cost-efficient, safe, and appropriate methods will be very useful for physicians to correctly identify the presence, size, and size of CVD targets in the vascular system. For physicians to distinguish between selected targets (such as CVD) ) And the blood vessels and each other, as well as distinguishing the remaining background tissue in the field of view, is further useful. Summary of the invention The present invention relates to MRI-based methods and systems that can be used for diagnosis And clinical assessment of the presence and size of intravascular CVDs, such as thrombus and atherosclerotic injury. Using the method and system of the present invention, improved anatomical information on cVDs can be obtained from vascular and standard MRI angiography, and this study It is more flexible and helps patients to handle it properly. Therefore, in one aspect of the present invention, a method for determining the presence or absence of a mammalian vascular internal fixation standard is proposed. The vascular internal fixation standard can be, for example, a tissue. Structure 'Cells' Cell surface and biopolymers ^ Examples of biological structures include CVDs' such as thrombus, atherosclerotic plaques, atherosclerotic hard paper scales Applicable to China National Standard (CNS) A4 (210X 297 mm) 1221406 A7 _ B7 V. Description of the invention (~~~ " Injury, tumor and thrombus plugging .. In addition, fixed targets can be biopolymers. Examples of biopolymers include lipids, lipoproteins, proteins, peptides 'And more.' If the biopolymer is a protein, it can be a protein present in CVDs at higher concentrations, including fibrin and collagen.

依據本發明一個具體實例，將標靶的MRI對比劑投予至哺乳動物。標靶的MRI對比劑對於固定標靶有特異親和力’且標靶的MRI對比劑，對於固定標靶及哺乳動物之血管系也可提供加強之對比。裝在一個具體實例中，標靶MRI對比劑對於固定標靶之特異親和力以解離常數表示，係少於50 # Μ。另外，標靶 MRI對比劑對固定標靶之特異親和力，以解離常數表示，少於5 ，或少於〇.5 /ζΜ。訂原則上’對固定標起呈現特異親和力之任何對比劑均可應用於本發明方法中。可用於本發明的標靶MRI對比劑某些結構包括：結構I :According to a specific example of the present invention, a target MRI contrast agent is administered to a mammal. Target MRI contrast agents have specific affinity for fixed targets' and target MRI contrast agents can also provide enhanced contrast for fixed targets and mammalian blood vessels. In a specific example, the specific affinity of the target MRI contrast agent for a fixed target is expressed as a dissociation constant, which is less than 50 #M. In addition, the specific affinity of the target MRI contrast agent for the fixed target is expressed as a dissociation constant, less than 5, or less than 0.5 / ζM. In principle, any contrast agent that exhibits a specific affinity for immobilization can be used in the method of the present invention. Some structures of the target MRI contrast agent that can be used in the present invention include: Structure I:

— -8 - 本紙張尺度適用中國國家標準((：；1^8) Α4規格(210 X 297公釐)— -8-This paper size applies to Chinese national standards ((:; 1 ^ 8) Α4 size (210 X 297 mm)

1221406 A71221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1221406 A7This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1221406 A7This paper size applies to China National Standard (CNS) A4 (210x 297 mm) 1221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1221406 A7This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝訂This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) binding

1221406 A7 ______ B7 五、發明説明（9 ) 對於上結構I-IX之額外資料示於u s•臨時案”以肽為基礎之多元標靶對比劑”，Zhang et al·，公告於2001年7月30 曰’ Ser· No· 60/308,721，以及在"以肽為基礎之多元標靶的對比劑"，Zhang et al·，與 U.S· Seir_ No. _—起公告，二者均以全文以參考方式納入。在一個具體實例中，標靶MRI對比劑投予之劑量應該在投藥後足以造成血中T丨值少於500毫秒。另外，標靶MRI對比劑投予之劑量應足以造成在投藥後少於300毫秒，或少於 175毫秒。典型而言，標靶MRI對比劑投予之劑量為由約 0.001至約500微莫耳/公斤。在另一具體實例中，劑量是由約0.001至約50微莫耳/公斤，或由約o.ooi至約5微莫耳/公斤。取得血管系造影第一組MRI數據。接下來取得固定標靶造影第二組MRI數據。第二組MRI數據取得之時間為適於提供固定標Ifc對比加強之可觀察水平，比較背景血液及組織加強而言。利用擾相梯度回波序列可得第二組MRI數據。在一個具體實例中，標靶MRI對比劑投予之劑量應足以造成固定標靶之丁〖少於500毫秒。另外，標靶MRI對比劑投予之劑量應足以造成固定標靶T!值少於300毫秒，或少於 100毫秒。在單一 MRI段落中可取得第一及第二組MRI數據。在一個具體實例中，單一MRI段落可持績少於6小時《另外，單一 MRI段落可持續少於4小時，或少於2小時，或少於1小 -13- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)1221406 A7 ______ B7 V. Description of the invention (9) Additional information on the upper structure I-IX is shown in us • Provisional case "Peptide-based multi-target contrast agent", Zhang et al., Announced in July 2001 30 "Ser · No · 60 / 308,721, as well as" Peptide-based Multiple Target Contrast Agents ", Zhang et al ·, and US · Seir_ No. _—announced, both in full text Included by reference. In a specific example, the target MRI contrast agent should be administered in a dose sufficient to cause a blood T T value of less than 500 milliseconds after administration. In addition, the target MRI comparator should be administered in a dose sufficient to cause less than 300 milliseconds, or less than 175 milliseconds after administration. Typically, the target MRI contrast is administered at a dose of from about 0.001 to about 500 micromoles / kg. In another specific example, the dose is from about 0.001 to about 50 micromoles / kg, or from about o.ooi to about 5 micromoles / kg. Obtain the first set of MRI data of angiography. Next, a second set of MRI data for fixed target angiography was obtained. The second group of MRI data was obtained at an observable level suitable to provide a fixed target Ifc contrast enhancement, comparing background blood and tissue enhancement. A second set of MRI data can be obtained using the spoiled gradient echo sequence. In a specific example, the target MRI contrast agent is administered in a dose sufficient to result in a fixed target of less than 500 milliseconds. In addition, the target MRI contrast should be administered in a dose sufficient to cause a fixed target T! Value of less than 300 milliseconds, or less than 100 milliseconds. The first and second sets of MRI data can be obtained in a single MRI segment. In a specific example, a single MRI paragraph can last less than 6 hours. In addition, a single MRI paragraph can last less than 4 hours, or less than 2 hours, or less than 1 hour.-13- This paper applies Chinese national standards. (CNS) A4 size (210 X 297 mm)

五、發明説明（ 10 ) 時。再比較第一及第二MRI數據組以決定血管系内固定標靶之存在，限制條件為第二MRI組已示出固定標靶之存在。例如，可將第一及第二MRI數據組混合產生第三MRI數據組，其中包括固定標靶及血管系之造影。第三數據組可示出固定標把之所在’若存在的話，在血管系内之所在。若欲求時，第三MRI數據組可呈現裝置上表現，以示出血管系内固定標靶之所在。第三MRI數據組也可示出血管系内固定標乾之大小。第一及第二MRI數據組可混合，即將第一及第二mri數據組就互相而言在空間上註明。混合步驟可進一步包括將第一或第二MRI數據組之空間幾些插補，如此第一及第二 MRI數據組有相當的空間解析。例如，吾等可決定第一及第二數據組何者有較高之空間解析，並將相當的其他數據組空間解析插補至較高空間解析。此外，吾等可將數據組與如此註明之個別數值組合生成之經修飾影像之直接估計組合，由第一及第二數據組來之數據元件予以插補。基於此’經修飾影像強度之直接估計可包括，將由第一及第二數據組來之註明的，插補的數據元件個別數值有變化地加重比例而得。除了其對固定標靶之特異親和力，標靶MRI對比劑也對存在於哺乳動物血管系内之非固定生物組份呈現出特異的親和力。存在於哺乳動物血管系内之非固定生物組份可為如：存在於血管液匯集内之蛋白質，如人類血清白蛋白， _ 14- 1221406V. Description of the invention (10). The first and second MRI data sets are then compared to determine the presence of fixed targets within the vascular system. The limitation is that the second MRI group has shown the presence of fixed targets. For example, the first and second MRI data sets can be mixed to generate a third MRI data set, which includes fixed targets and angiography of the vascular system. The third data set may indicate where the fixed marker is located, if present, within the vascular system. If desired, a third MRI data set can be presented on the device to show where the target is fixed in the vascular system. The third MRI data set can also show the size of the fixed standard in the vascular system. The first and second MRI data sets can be mixed, ie the first and second mri data sets are spatially noted in terms of each other. The mixing step may further include interpolating the space of the first or second MRI data sets, so that the first and second MRI data sets have considerable spatial resolution. For example, we can decide which of the first and second data sets has a higher spatial resolution, and interpolate the equivalent spatial resolution of other data sets to a higher spatial resolution. In addition, we can combine the direct estimation combination of the modified image generated by combining the data set with the individual numerical values so noted, and the data elements from the first and second data sets are interpolated. The direct estimation of the intensity of this modified image may include the proportions of the individual values of the interpolated data elements that are noted from the first and second data sets are changed with varying proportions. In addition to its specific affinity for fixed targets, target MRI contrast agents also exhibit specific affinity for non-fixed biological components present in mammalian blood vessels. Non-fixed biological components present in mammalian vascular systems may be, for example, proteins present in vascular fluid pools, such as human serum albumin, _ 14-1221406

血纖維蛋白原，酸性醣蛋白，球蛋白，及脂蛋白。本發明的另一目的是提出決定哺乳動物血管系内固定標靶存在與否之方法，其中對哺乳動物投予標靶的MM對比劑及血管MRI對比劑。方法包括對哺乳動物投予標靶的 MRI對比劑。標靶的對比劑對固定標靶具有特異親和力，且“ I&對比劑可對固定標把提供對比加強作用。在血管系内之固定標靶可為組織，生物結構，細胞，細胞表面，及生物聚合物。在其中固定標靶是生物結構之具體實例中，生物結構可為與CVD有關之結構，如血栓，動脈粥樣硬化斑，動脈粥樣硬化傷害，腫瘤，及血栓插栓。另外’固定標靶可為生物聚合物《與CVDs有關之生物聚合物貫例有脂質’脂蛋白，蛋白質，多肽及多醣。若固定標把是生物聚合物，生物聚合物通常是以高濃度存在於CVDs 中之蛋白質，如血纖維蛋白及膠原蛋白。標靶MRI對比劑投予之劑量為足以造成固定標靶之τ ι值少於500毫秒。在一個具體實例中為少於3〇〇毫秒，或少於 10 0毫秒。標靶MRI對比劑對固定標靶可呈現特異親和力。在一些具體實例中，標靶MRI對比劑之特異親和力以解離常數表示是少於50 /zM。在另一具體實例，特異親和力少於5 。又另一具體實例中是少於0.5 βΜ。可用於本發明之標靶MRI對比劑結構實例包括： -15- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)Fibrinogen, acid glycoprotein, globulin, and lipoprotein. Another object of the present invention is to propose a method for determining the presence or absence of a fixed target in a mammalian vascular system, in which a target MM contrast agent and a vascular MRI contrast agent are administered to a mammal. Methods include administering a target MRI contrast agent to a mammal. Target's contrast agent has specific affinity for fixed targets, and "I & contrast agents can provide contrast-enhancing effects on fixed targets. Fixed targets in blood vessels can be tissues, biological structures, cells, cell surfaces, and Biopolymer. In a specific example where the fixed target is a biological structure, the biological structure may be a structure related to CVD, such as thrombus, atherosclerotic plaque, atherosclerotic injury, tumor, and thrombus plug. 'Fixed targets can be biopolymers. Biopolymers related to CVDs have lipids' lipoproteins, proteins, peptides, and polysaccharides. If fixed targets are biopolymers, biopolymers are usually present at high concentrations. Proteins in CVDs, such as fibrin and collagen. The target MRI contrast agent is administered in a dose sufficient to cause a fixed target with a τ ι value of less than 500 milliseconds. In a specific example, it is less than 300 milliseconds, Or less than 100 milliseconds. Target MRI contrast agents can exhibit specific affinity for fixed targets. In some specific examples, target MRI contrast agents have specific affinity to dissociate The number is less than 50 / zM. In another specific example, the specific affinity is less than 5. In another specific example, it is less than 0.5 βM. Examples of the structure of the target MRI contrast agent that can be used in the present invention include: -15- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

裝訂Binding

1221406 A71221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐）This paper size applies to China National Standard (CNS) A4 (210x 297 mm)

裝訂Binding

1221406 A71221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1221406 A7 _________ B7 五、發明説明（16 ) 及結構IX :This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 1221406 A7 _________ B7 V. Description of Invention (16) and Structure IX:

裝訂如先前所示，結構I -1X揭示於美國臨時案”以肽為基礎之多元標靶之對比劑”，Zhang et al.，公告於2001年7月30 曰，Ser· No· 60/3 08,721，及在"以肽為基礎之多元標靶之對比劑”，Zhang et al·，與此同時公告，U.S· Ser· No. -’二者均以全文以參考方式納入本案。Binding As shown previously, the structure I -1X is disclosed in the US provisional case "Peptide-based Multiple Target Contrast Agents", Zhang et al., Published July 30, 2001, Ser. No. 60/3 08,721, and "Peptide-based Contrast Agents for Multiple Targets", Zhang et al., Meanwhile, announced that US · Ser · No.-'Both are incorporated into this case by reference in their entirety.

依據方法，血管MRI對比劑也投予至哺乳動物。血管對比劑可提供哺乳動物血管系對比之加強。血管MRI對比劑以足以在投予後造成血液中Τ丨值少於30〇毫秒之劑量投予。另外，血管MRI對比劑以足以在投藥後造成血中Τ丨值少於175毫秒，或少於1 〇〇毫秒之劑量投予。血管MRI對比劑可以是一種細胞外mri對比劑。此細胞外MRI對比劑之實例包括如： __-20- 本紙張尺度逋用中國國家標準(CNS) A4規格(210 X 297公釐） 1221406 A7 B7 五、發明説明（17 ,C02 O2Cm^c〇2-According to the method, a vascular contrast agent is also administered to a mammal. Vascular contrast agents provide enhanced contrast in mammalian vascular systems. An angiographic contrast agent is administered in a dose sufficient to cause a T0 value in the blood of less than 30 milliseconds after administration. In addition, vascular MRI contrast agents are administered at a dose sufficient to cause a blood T1 value of less than 175 milliseconds, or less than 1000 milliseconds after administration. The vascular contrast agent may be an extracellular mri contrast agent. Examples of this extracellular MRI contrast agent include: __- 20- Chinese paper standard (CNS) A4 size (210 X 297 mm) used in this paper size 1221406 A7 B7 V. Description of the invention (17, C02 O2Cm ^ c. 2-

Gd3 c〇2' (Gd-DTPA), C〇2* C02' .N N、 Gd3+ /—co2- o2o c〇2 (Gd-DOTA), 严2-Gd3 c〇2 '(Gd-DTPA), C〇2 * C02' .N N, Gd3 + / —co2- o2o c〇2 (Gd-DOTA), Yan 2-

CH3NHOC—y /~\\/~\ /—CONHCH3 N N (Gd-DTPA-BMA)， f Gd3+ 1 co2· co2' 02C-CH3NHOC—y / ~ \\ / ~ \ / —CONHCH3 N N (Gd-DTPA-BMA), f Gd3 + 1 co2 · co2 '02C-

C02* Gd3+〕〇H ；N H CH3 c°2' (Gd-HP-D03A)， .CO2* CH3OCH2CH2NHOC—'V /~\|/~\ /—conhch2ch2och3 N N N、 (Gd3+ ^ C02" C02· (gadobutol). -21 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐） (gadoversetamide), 及C02 * Gd3 +] 〇H; NH CH3 c ° 2 '(Gd-HP-D03A), .CO2 * CH3OCH2CH2NHOC—'V / ~ \ | / ~ \ / —conhch2ch2och3 NNN, (Gd3 + ^ C02 " C02 · (gadobutol) -21-This paper size is applicable to Chinese National Standard (CNS) A4 (210x 297 mm) (gadoversetamide), and

OH 1221406 A7 B7 五、發明説明（18 ) 另外，血管MRI對比劑可以是一種鐵粒子，包括如氧化鐵之超小粒子（USPIOs)，及單晶體氧化鐵粒子（MIONs)。又在另一具體實例中，血管MRI對比劑是血液匯集對比劑。可用於本發明之血液匯集對比劑某些結構為： Gadomer-17, P760OH 1221406 A7 B7 V. Description of the invention (18) In addition, the vascular MRI contrast agent can be an iron particle, including ultra-small particles (USPIOs) such as iron oxide, and single crystal iron oxide particles (MIONs). In yet another specific example, the vascular MRI contrast agent is a blood pooling contrast agent. Some structures of the blood pooling contrast agent that can be used in the present invention are: Gadomer-17, P760

(Gd-EOB-DTPA),(Gd-EOB-DTPA),

-22- 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1221406 ^〇·-22- This paper size applies to China National Standard (CNS) A4 (210x 297 mm) 1221406 ^ 〇 ·

-〇2〇 (B-22956/1). A7 B7 五、發明説明（19 ) 〇〆-〇2〇 (B-22956 / 1). A7 B7 V. Description of the invention (19) 〇〆

(MS-325)，及(MS-325), and

、C〇2- 、C〇2- 血管MRI對比劑也可對存在於哺乳動物血管系内之非固定生物組份呈現特異的親和力。存在於哺乳動物血管系内之非固定蛋白質實例包括存在於血液及血清内之蛋白質，如人類血清白蛋白，血纖維蛋白原，α -酸性糖蛋白，球蛋白及脂蛋白。 -23- 本紙張尺度適用中國國家標準(CNS) Α4規格(210Χ 297公釐）, C02-, C02-vascular MRI contrast agents can also exhibit specific affinity for non-fixed biological components present in mammalian vascular systems. Examples of non-fixed proteins present in mammalian blood vessels include proteins present in blood and serum, such as human serum albumin, fibrinogen, α-acid glycoprotein, globulin, and lipoprotein. -23- The size of this paper applies to China National Standard (CNS) A4 (210 × 297 mm)

1221406 A7 B71221406 A7 B7

標靶之MRI對比劑投予之劑量可由約〇〇〇1至約5〇〇微莫耳/公斤，且血管MRI對比劑投予之劑量可由約〇〇1至約 300微莫耳/公斤。在另一具體實例中，標靶MR][對比劑投予之劑量為由約0.001至約50微莫耳/公斤，且血管MRI對比劑投予之劑量為由約0.01至約30微莫耳/公斤。另外，標靶MRI對比劑投予之劑量可由約〇〇〇1至約5微莫耳/公斤，且血管MRI對比劑投予之劑量為由約〇 ·〇 1至約3微莫耳/公斤。可得到包括有血管造影之血管MRI數據組，及包括有固定標把造影之標乾MRI數據組。標把數據組在適於提供固定標靶對比加強之可觀察水平時獲得，此相較於背景血液及組織加強而言。在某些具體實例中，標靶MRI數據組利用擾相梯度回波序列獲得。在一個具體實例中，標靶對比劑在血管對比劑之劑投予，且在血管MRI數據組前取得標靶MRI數據組。另外，標靶對比劑及血管對比劑可同時投予，且血管MRI數據組在標靶MRI數據組之前獲得。在一個具體實例中，標靶及血管數據組可在單一 MRI段落中獲得。標靶對比劑及血管對比劑互相可在2小時内投予。另外，標靶對比劑及血管對比劑可互相在3 0分鐘内投予，或互相在1 5分鐘内《血管MRI對比劑可以快速濃注或輸液方式投藥。若採輸注方式，可使用少於1 5分鐘之輸液時間。在另一具體實例，輸注時間可少於1 0分鐘，或少於3分鐘。可比較血管及標靶MRI數據組以決定血管系内固定標靶 ____-24- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)The target MRI contrast agent can be administered at a dose of from about 0.001 to about 5,000 micromoles / kg, and the vascular contrast agent can be administered at a dose of about 0.001 to about 300 micromoles / kg. In another specific example, the target MR] [contrast agent is administered at a dose of from about 0.001 to about 50 micromoles / kg, and the vascular MRI contrast agent is administered at a dose of from about 0.01 to about 30 micromoles /kg. In addition, the target MRI contrast agent can be administered at a dose of about 0.001 to about 5 micromoles / kg, and the vascular MRI contrast agent can be administered at a dose of about 0.001 to about 3 micromoles / kg. . Vascular MRI data sets including angiography and standard MRI data sets including fixed calibration angiography are available. Target data sets are obtained at an observable level suitable to provide contrast enhancement of fixed targets, as compared to background blood and tissue enhancement. In some specific examples, the target MRI data set is obtained using a spoiled gradient echo sequence. In a specific example, the target contrast agent is administered as a vascular contrast agent, and the target MRI data set is obtained before the vascular MRI data set. In addition, the target contrast agent and the vascular contrast agent can be administered at the same time, and the vascular MRI data set is obtained before the target MRI data set. In a specific example, the target and vascular data sets can be obtained in a single MRI segment. Target contrast agent and vascular contrast agent can be administered to each other within 2 hours. In addition, the target contrast agent and vascular contrast agent can be administered within 30 minutes of each other, or within 15 minutes of each other. The vascular MRI contrast agent can be administered by rapid infusion or infusion. If infusion is used, an infusion time of less than 15 minutes can be used. In another specific example, the infusion time may be less than 10 minutes, or less than 3 minutes. The MRI and target MRI data sets can be compared to determine the target for internal fixation in the vascular system ____- 24- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

裝訂Binding

A7 B7 五、發明説明（21 ) 之存在，限制條件為標靶MRI數據組示出固定標靶之存在也可w合血管及標把MRI數據組例如，血管及標乾 MRI數據組可混合以產生第三MRI數據組，其包括固定標乾及血管系之造影。第三數據組也可示出血管系統内固定標乾之所在及大小。若欲求時，第三MRI數據組可在成像裝置上表現，以示出血管系統内固定標靶之所在及大小。數據組可互相空間上註明標靶及血管MRI數據組而組合。組合步驟也包括將血管或標把MRI數據組任一之空間解析插補，如此血管及標靶MRI數據組為相當的空間解析。在一個具體實例中，吾等可決定血管或標靶MRI數據組何者有較高之空間解析；且再將相當的其他數據組空間解析或較高之空間解析。另外，混合步驟進一步包括將經修飾造影強度直接估計，其來自血管及標靶MRI數據組如此註明且插補之數據元件個別組合。在一個具體實例中，經修飾造影強度之直接計算包括將來自血管及標靶MR][數據組之經註明，插補數據元件個別數值予以有變化地加 4^ ° 除非另有所定義，此中所用的所有技術及科學術語具有屬於本發明一般精藝者可了解之相同定義。在實行或測試本發明中雖然可使用和此中所述相似或相當的方法及材料’但以下仍詳述適合的方法及材料。所有的刊物，專利案’專利及此中所述之其他參考文獻，也以全文列為本案參考。右有衝突時’本說明書包括定義可主控。此外，方法’材料及實例僅供說明不欲予以限制。 —-25- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1221406 A7 __B7___五、發明説明（22 ) 在本揭示中並未明白定義的常用化學縮寫，可見於美國化學協會之 The American Chemical Society Style Guide， Second Edition; American Chemical Society, Washington, D.C. (1997); ”2001 Guidelines for Authors，’’ J. Org. Chem· 66 (1)，24A (2001);及"A Short Guide to Abbreviations and Their Use in Peptide Science.f, J. Peptide Sci. 5, 465-471 (1999) 0 本發明許多具體實例詳述示於附圖及下文。而由說明書，附圖及申請專利範圍，本發明其他特色，主題及優點可更加明白。附圖說明圖1是代表本發明一個具體實例之流程。圖2A示出標靶對比劑訊號強度（任意單位，a.u.)對時間之作圖，其存在於血管系（如靜脈）或結合至固定標靶，其中標靶對比劑之劑量投予至病人足以適度加強固定標靶及血管系（如靜脈）。圖2B示出標靶對比劑訊號強度（任意單位，a.u.)對時間之作圖’其存在於血管系（如靜脈）中或結合至固定標靶，其中標靶對比劑投予之劑量較加強血管系所需的還少，且第二作用物（如血管作用物）在標靶作用物之前投予提供血管系對比之加強（如靜脈）。圖3為說明混合本發明MRI數據組方法的一個具體實例流程。圖4 A是因標靶MRI對比劑之結合而加強之固定標靶MRI -26· 本紙張尺度適用中國國家操準(CNS) A4規格(210X 297公釐）A7 B7 V. Existence of invention description (21), the limitation is that the target MRI data set shows the existence of a fixed target. The blood vessel and target MRI data set can also be combined. For example, the blood vessel and standard MRI data set can be mixed with A third MRI data set is generated, which includes fixed standard and angiography of the vascular system. The third data set can also show the location and size of fixed targets in the vascular system. If desired, a third MRI data set can be represented on the imaging device to show the location and size of the fixed target within the vascular system. The data sets can be spatially marked with target and vascular MRI data sets. The combining step also includes spatially interpolating either the blood vessel or the target MRI data set, so that the blood vessel and the target MRI data set are equivalent to the spatial analysis. In a specific example, we can determine which of the vascular or target MRI data sets has a higher spatial resolution; and then parse the equivalent other data sets spatially or a higher spatial resolution. In addition, the blending step further includes a direct estimation of the modified contrast intensity from individual combinations of the data elements of the vascular and target MRI data sets noted and interpolated as described herein. In a specific example, the direct calculation of the modified angiographic intensity includes annotating the individual values of the data element from the vascular and target MR] [data set, plus 4 ^ ° unless otherwise defined, this All technical and scientific terms used in this article have the same definitions as those of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described in detail below. All publications, patents' patents and other references mentioned herein are also incorporated by reference in their entirety. Right when there is a conflict 'This manual includes definitions that can be controlled. In addition, the method 'materials and examples are illustrative only and are not intended to be limiting. —-25- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1221406 A7 __B7___ V. Description of the invention (22) Common chemical abbreviations that are not clearly defined in this disclosure can be found in the United States The American Chemical Society Style Guide, Second Edition; American Chemical Society, Washington, DC (1997); "2001 Guidelines for Authors," J. Org. Chem. 66 (1), 24A (2001); and & quot A Short Guide to Abbreviations and Their Use in Peptide Science.f, J. Peptide Sci. 5, 465-471 (1999) 0 Many specific examples of the present invention are shown in detail in the drawings and below. The scope of the patent application, other features, themes and advantages of the present invention can be more clearly understood. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flow chart representing a specific example of the present invention. FIG. 2A shows the target contrast signal strength (arbitrary unit, au) versus time. Mapping, which exists in vascular systems (such as veins) or is bound to fixed targets, where the target contrast agent dose is administered to the patient enough to moderately strengthen the fixed targets and vascular systems (such as veins). 2B shows a plot of target contrast signal strength (arbitrary unit, au) versus time, which is present in a vascular system (such as a vein) or is bound to a fixed target, where the target contrast agent is administered in a dose that strengthens the blood vessel Fewer systems are needed, and a second agent (such as a vascular agent) is administered before the target agent to provide enhancement of the vascular system contrast (such as a vein). Figure 3 illustrates one method of mixing the MRI data set of the present invention. Specific example process. Figure 4 A is a fixed target MRI enhanced by the combination of the target MRI contrast agent. -26 · This paper size applies to China National Standards (CNS) A4 specifications (210X 297 mm)

裝訂線·Binding Line ·

1221406 A7 ____B7 五、發明説明（23 ) 造影（在此是血栓）。圖4 B是投予血管對比劑而加強血管系之MRI造影。圖5是將在圖4A及4B之數據組組合成第三數據組之具體實例，證明固定標靶及血管系統之造影，並顯示出血管系内固定標靶之所在。圖6 A是投予標把對比劑而加強之血管系MRI造影。圖6 B是由結合標靶的MRI對比劑而加強之固定標靶（在此為血栓）之MRI造影。圖7是組合於圖6A及6B之數據組而成之第三數據組之具體實例，證明固定標靶及血管系之造影，並顯示出血管系内固定標把之所在" 在各附圖中類似的參考符號表示類似元件。詳細說明定義特異的親和力-如此中所用，特異的親和力指對比劑非共價結合至特殊固定標的之能力，包括組成固定標靶之一種以上的生物組份，其程度勝於其他化合物。特異的親和力常就平衡解離常數，kd而偵測。特異的親和力，如此中所用，特異地並不指某些對比劑（如USPIOs或MIONs)為網狀内皮系統（RES)及/或單核呑噬細胞系統（MPS)之細胞所攝入或呑嗤之機制。固定標靶-固定標靶，如此中所用是一種在哺乳動物血管系内之生物組份，其在MRI段落中於可定義其所在之血管系内X，Y及Z軸任一者上不會進行顯著的移動或旋轉運 -27- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 12214061221406 A7 ____B7 V. Description of the Invention (23) Contrast (thrombus here). Fig. 4B is an MRI contrast enhanced vascular system administered with a vascular contrast agent. Fig. 5 is a specific example of combining the data sets in Figs. 4A and 4B into a third data set, demonstrating the imaging of the fixed target and the vascular system, and showing the location of the fixed target in the vascular system. Fig. 6A is an enhanced MRI angiography of contrast vessels administered with a standard contrast agent. Figure 6B is an MRI contrast of a fixed target (here, a thrombus) enhanced by a target-bound MRI contrast agent. Fig. 7 is a concrete example of a third data set combined with the data sets of Figs. 6A and 6B, demonstrating the fixed target and the angiography of the vascular system, and showing the location of the vascular internal fixation marker " Similar reference symbols in the like designate similar elements. Detailed Description Definition Specific Affinity-As used herein, specific affinity refers to the ability of a contrast agent to non-covalently bind to a particular fixed target, including more than one biological component that makes up the fixed target, to a greater degree than other compounds. The specific affinity is often detected by the equilibrium dissociation constant, kd. Specific affinity, as used herein, does not specifically mean that certain contrast agents (such as USPIOs or MIONs) are taken up by or ingested by cells of the reticuloendothelial system (RES) and / or monocyte phagocytic system (MPS)机制 mechanism. Fixed target-fixed target, as used here is a biological component in mammalian blood vessels, which will not be defined in any of the X, Y, and Z axes of the blood vessel in which it can be defined in the MRI paragraph Significantly move or rotate -27- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1221406

動田〃平估固疋標祀的任何運動時，由於哺乳動物呼吸，血管内血流’哺乳動物身體的移動，或置於動物或動物血管系上《外在壓力戶斤致之固定標祀之任何移動或旋轉運動均應予以排除。在特殊時間時，某些固定㈣可視為在血管系内實質上是於空間上固定的，如血栓。非固定標靶-非固定標靶如此中所用的是固定標靶血管系内的生物組份，其可在定義其所在之X , 丫及2軸上於任何時間上進>ί亍顯奢的移動或旋轉運動。多肽-如此中所用的多肽表示長於約3個胺基酸之胺基酸鏈，其可包括非天然胺基酸，且估不論轉譯後或合成後之修飾或處理。生物聚合物-如此中所用的，生物聚合物表示聚合物質，其通常可在生物系統中自然形成。某些生物聚合物可自明確的組成亞單位所構成，並加上連接亞單位的一般官能基，如蛋白質或多肽通常由一組亞單位胺基酸（天然及非天然的）在醯胺鍵連接亞單位下構築而成。生物結構-如此中所用，生物結構是存在於哺乳動物血管系内之物理性結構，通常構築自均勾或非均勻的，共價或非共價鏈結生物組份。血液匯集之對比劑-如此中所用的，血液匯集對比劑表示較細胞外作用物更長時間保留在血液匯集之内。血液匯集作用物基於許多理由保留在血液匯集内，如分子大小及分子量，或對於血液匯集或血管系内某些組份之特異親和力0 -28- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)At any time, the movement of the target is fixed, because of mammalian breathing, intravascular blood flow, the movement of the mammal ’s body, or the placement of the fixed target on the animal or animal vascular system. Any movement or rotation shall be excluded. At certain times, some fixed ridges can be considered to be essentially spatially fixed within the vasculature, such as blood clots. Non-fixed target-Non-fixed target is used in this way is the biological component in the fixed target vascular system, which can be defined at any time on the X, Y and 2 axes where it is defined > Moving or rotating motion. Polypeptide-A polypeptide as used herein means an amino acid chain longer than about 3 amino acids, which may include unnatural amino acids, and is estimated to be modified or processed after translation or after synthesis. Biopolymer-As used herein, biopolymer refers to a polymeric substance that can generally be formed naturally in biological systems. Some biopolymers can be composed of well-defined subunits, and add general functional groups to connect the subunits, such as proteins or polypeptides. Generally, a group of subunit amino acids (natural and unnatural) are bonded to the amine bond. Constructed by connecting subunits. Biological structure-As used herein, a biological structure is a physical structure that exists in the mammalian vascular system and is usually constructed from homogeneous or non-uniform, covalently or non-covalently linked biological components. Blood pooling contrast agent-As used herein, blood pooling contrast agent is meant to remain within the blood pool for longer than an extracellular substance. Blood pooling agents remain in the blood pool for many reasons, such as molecular size and molecular weight, or specific affinity for certain components in the blood pool or vascular system. 0 -28- This paper applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm)

裝訂Binding

1221406 A7 B7 五、發明説明（25 ) 細胞外對比劑-如此中所用的，細胞外對比劑指對存在於血管系内之生物組份不呈現顯著特異親和力之對比劑，包括存在於血管系内之生物結構或生物聚合物，且並不保留在血液中顯著時間。如此中所用的，"Gd”表示金屬釓之離子型式，如離子型式在此可書寫成Gd(III)，Gd3+，gad0等，在所意涵之離子型式中並無差別。本發明是有關以MRI -為基礎之方法及系統，可用於診斷及臨床評估於血管系内CVDs如血检及動脈粥樣硬化傷害之存在’所在及大小。使用本發明方法及系統，可改進自血管及標靶MRI造影中所得之關於CVDs之解剖資料，使醫師可發展更有效率的治療計劃。標靶MRI齎比劑之用法因此，本發明的一方面是提出決定哺乳動物血管系内固定標靶存在與否之方法。在一個具體實例中，本發明方法涉及在投予標靶MRI對比劑後取得二組MRI數據。一般而言，標靶對比劑在取得數據前，投予至疑似有CVD之哺乳動物（如病人）。在血管系内之固定標靶可為組織，生物結構，細胞，細胞表面及生物聚合物。生物結構之實例包括CVDs，如血栓，動脈粥樣硬化斑，動脈粥樣硬化傷害，腫瘤，及血栓插栓。另外，固定標靶可為生物聚合物。生物聚合物之實例包括脂質，脂蛋白，蛋白質，多肽，及多醣。若生物聚合物是蛋白質，其可為通常以高濃度存在於CVDs之蛋白 ___ -29- ____ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）1221406 A7 B7 V. Description of the invention (25) Extracellular contrast agent-As used herein, extracellular contrast agent refers to a contrast agent that does not exhibit significant specific affinity for biological components present in the vascular system, including in the vascular system Biological structure or biopolymer and does not remain in the blood for significant time. As used herein, " Gd " means the ionic form of metal rhenium. For example, the ionic form can be written as Gd (III), Gd3 +, gad0, etc. There is no difference in the meaning of the ionic form. The present invention is related MRI-based methods and systems can be used to diagnose and clinically assess the presence and size of CVDs in blood vessels such as blood tests and atherosclerotic injuries. Using the method and system of the present invention, self-vessels and targets can be improved. The anatomical data of CVDs obtained from target MRI imaging allow physicians to develop more efficient treatment plans. Use of target MRI 赍 ratio agents Therefore, one aspect of the present invention is to propose the determination of the existence of fixed targets in the mammalian vascular system. The method of whether or not. In a specific example, the method of the present invention involves obtaining two sets of MRI data after the target MRI contrast agent is administered. In general, the target contrast agent is administered to a suspected CVD before obtaining the data. Mammals (eg patients). Fixed targets in the vascular system can be tissues, biological structures, cells, cell surfaces and biopolymers. Examples of biological structures include CVDs, such as thrombi Atherosclerotic plaques, atherosclerotic injuries, tumors, and thrombus plugs. In addition, fixed targets can be biopolymers. Examples of biopolymers include lipids, lipoproteins, proteins, peptides, and polysaccharides. If biological The polymer is a protein, which can be a protein that is usually present in CVDs at a high concentration ___ -29- ____ This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

裝訂Binding

1221406 A7 B7 五、發明説明（26 ) 質，包括如：血纖維蛋白及膠原蛋白。依據本發明的一個具體實例，標靶MRI對比劑投予至哺乳動物。標靶MRI對比劑對於固定標靶有特異的親和力’ 且標靶MRI對比劑也可提供哺乳動物固定標靶及血管系内之對比加強。在一個具體實例中，標靶MRI對比劑對於固定標靶之特異親和力，以解析常數表示，係少於5 0 。另外，標靶MRI對比劑對於固定標靶之特異親和力’以解離常數表示，係少於5 或少於0.5 /ζΜ。可用於本發明之某些標靶MRI對比劑對於固定標靶有特異的親和力，包括在CVD中之生物組份或存在其内之結構 (如血检，斑，或動脈粥樣硬化傷害），且包括血纖維蛋白結合對比劑，述於WO 01/08712及WO 01/09188(以全文列為本案參考）；血纖維蛋白標把對比劑，述於Lanza et al·， Acad· Radiol· 5(suppl 1): S173-S176 (1998)及 Yu et al·， Magnetic Resonance in Medicine 44: 867-872 (2000) » Johansson et al·，之血小板標把粒子，J· Mag· Res· Imaging 13: 615-618 (2001) ; Sipkins et al·，之整合素標靶作用物，Nature Medicine 4(5):623-626 (1998) ; Sipkins et al·，之 ICAM -1 標把作用物，J. Neuroimmunol· 104: 1-9 (2000) :對準斑或感染之巨嗤細胞，WMooreetal.，JMRI7:1140-1 145 (1997);針對心肌梗塞之抗-肌蛋白作用物，如 Weissleder et al., Radiology 181: 245-249 (1991) ； Kornguth et al·，之淋巴細胞特異的作用物，…J· Neurosurg 66: 8980906 (1987) ; Schmitz et al·，之斑標把作用物，Investigative -30- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）1221406 A7 B7 V. Description of the invention (26) Properties, such as: fibrin and collagen. According to a specific example of the present invention, a target MRI contrast agent is administered to a mammal. Target MRI contrast agents have specific affinity for fixed targets', and target MRI contrast agents can also provide enhanced contrast in mammalian fixed targets and blood vessels. In a specific example, the specific affinity of the target MRI contrast agent for the fixed target is expressed as an analytical constant, which is less than 50. In addition, the specific affinity of the target MRI contrast agent for a fixed target is expressed as a dissociation constant, which is less than 5 or less than 0.5 / ζM. Certain target MRI contrast agents useful in the present invention have specific affinity for fixed targets, including biological components in CVD or structures present within them (such as blood tests, plaques, or atherosclerotic injuries), It also includes fibrin binding contrast agents, described in WO 01/08712 and WO 01/09188 (the entire text is incorporated herein by reference); fibrin labelled contrast agents are described in Lanza et al., Acad. Radiol. 5 ( suppl 1): S173-S176 (1998) and Yu et al., Magnetic Resonance in Medicine 44: 867-872 (2000) »Johansson et al., Platelet Target Particles, J. Mag. Res. Imaging 13: 615 -618 (2001); Sipkins et al., An integrin target, Nature Medicine 4 (5): 623-626 (1998); Sipkins et al ,, an ICAM -1 target, J. Neuroimmunol 104: 1-9 (2000): spotted or infected giant salamander cells, WMooreetal., JMRI 7: 1140-1 145 (1997); anti-muscle agents for myocardial infarction, such as Weissleder et al. ,, Radiology 181: 245-249 (1991); Kornguth et al., Lymphocyte-specific agents, ... J. Neurosurg 66: 8980906 (1987); Schmitz et al., Spot Marker, Investigative -30- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

裝訂Binding

線 1221406 A7 B7 五、發明説明（27 )Line 1221406 A7 B7 V. Description of the invention (27)

Radiology 35(8):460-471 (2000);及 Ruehm 之斑標祀作用物，Circulation: 415-422 (June 23，2001 ) 〇特言之，可用於本發明方法的標靶MRI對比劑某些結構包括以下：結構I :Radiology 35 (8): 460-471 (2000); and Ruehm's spot target, Circulation: 415-422 (June 23, 2001). In particular, a target MRI contrast agent that can be used in the method of the present invention These structures include the following: Structure I:

_-31 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1221406 A7_-31-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1221406 A7

本紙張尺度逋用中國國家標準(CNS) A4規格(210 x 297公釐) 1221406 A7This paper uses China National Standard (CNS) A4 (210 x 297 mm) 1221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1221406 A7 B7 五、發明説明（31 ) 及結構IX :This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1221406 A7 B7 V. Description of the invention (31) and structure IX:

如先前所述，上結構I-IX揭示於美國臨時案"以肽為基礎之多元標靶對比劑"，Zhang et al·，公告於2001年7月30 曰，Ser. No. 60/308,721，及”以肽-為基礎之多元標靶的對比劑"，Zhang et al·,，在此一起公告U.S. Ser No. _，其二者以全文列為本案參考。投予至哺乳動物之標靶MRI對比劑，其劑量較用來顯影血管系之MRI對比劑一般劑量還小。為使血管造影充份加強，標靶MRI對比劑投予之劑量應是足以造成血中τ丨值即血中水質子弛緩時間’少於500毫秒之量《另外，標纪MRI 對比劑投予之劑量應足在投藥後可造成血中Τ ι值少於3〇〇毫秒，或造成投藥後血中Tl少於175毫秒之量。典型而呂，標IfcMRI對比劑投予之量為由約〇〇〇1至約5〇〇微莫耳/ 公斤。在其他具體實例中，劑量為由約〇〇〇1至約5〇〇微莫耳/公斤，或由約0.001至約5微莫耳/公斤。As mentioned earlier, the above structure I-IX is disclosed in the US provisional case "Peptide-based Multiple Target Contrast Agents", Zhang et al., Published July 30, 2001, Ser. No. 60 / 308,721, and "Peptide-based Multiple Target Contrast Agents", Zhang et al., Hereby published US Ser No. _, both of which are incorporated herein by reference in their entirety. Administration to mammals The dose of the target MRI contrast agent is smaller than the general dose of the MRI contrast agent used to develop the vascular system. In order to fully enhance the angiography, the dose of the target MRI contrast agent should be sufficient to cause a blood τ 丨 value That is, the amount of water proton relaxation time in blood is less than 500 milliseconds. In addition, the standard MRI contrast agent should be administered in a dose sufficient to cause a blood T Ti value of less than 300 milliseconds after administration, or cause blood after administration. The amount of Tl is less than 175 milliseconds. Typically, the standard ifcMRI contrast agent is administered in an amount of from about 0.001 to about 5,000 micromoles / kg. In other specific examples, the dose is 0.001 to about 500 micromoles / kg, or from about 0.001 to about 5 micromoles / kg.

1221406 A7 B7 五、發明説明（32 ) 在投予標靶MRI對比劑後不同時間，取得血管系第一組 MRI造影數據組。接下來，取得固定標靶第二組MRI造影數據組。在適於提供固定標把對比加強可觀察水平之時間點時取得第二MRI數據，此相較於背景血液及組織加強而言。取得第一及第二組數據之時間點，依血液中標靶對比劑之濃度，標靶對比劑滲透至固定標靶之速率，及標靶對比劑對固定標靶之特異親和力而定。此參數若未提供特異對比劑使用，可由初步投予作用物及隨時間造影之更臻完善步驟來決定。在某些具體實例中，造影標靶之最佳時間是當標靶之訊號強度近其高峰時，或當和背景血液及組織加強作用比較下有最大對比加強作用之時。可依據病人欲具象化之身體面積，及血管系欲求之期待及固定標的之組成而定，應用不同的MRI造影採集參數。這些參數包括磁共振（MR)，就弛緩時間而言特示之波序，重覆時間（TR)，回波時間（TE)，置換角度，欲求之影像解析度，次元及視野。波序是用在欲顯影原子中，擾亂核方位的一種RF脈衝。一旦將波序通過病人，此核會掉回外在磁場，且一直如此，使放射-頻率能量可以訊號方式被放出，之後接收線圈可測及，最終可產生欲求之MRA影像。而弛緩時間是核回復至正常位置所需之時間，可應用多種弛緩時間模式，各自會產生不同的磁化距特性及狀況。典型的弛緩時間包括：Τι，T2及T2*。最後，重覆時間（TR)是應用各RF脈衝之時間間隔，回波時間（ΤΕ)是激發脈衝以及再發射波之 -36- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐)1221406 A7 B7 V. Description of the invention (32) Different time after the target MRI contrast agent was administered, the first group of MRI angiography data sets of the vascular system was obtained. Next, a second set of MRI contrast data sets for the fixed target was obtained. Second MRI data is obtained at a point in time when it is appropriate to provide a fixed target to enhance the observable level compared to background blood and tissue enhancement. The time points for obtaining the first and second sets of data depend on the concentration of the target contrast agent in the blood, the rate at which the target contrast agent penetrates into the fixed target, and the specific affinity of the target comparator for the fixed target. If this parameter is not provided with a specific contrast agent, it can be determined by preliminary administration of the agent and better steps of imaging over time. In some specific examples, the optimal time to contrast the target is when the signal strength of the target is near its peak, or when there is a maximum contrast enhancement effect compared to the background blood and tissue enhancement effect. Depending on the patient's body area to be visualized, the desire of the vascular system, and the composition of the fixed target, different MRI imaging acquisition parameters can be applied. These parameters include magnetic resonance (MR), wave order specific in terms of relaxation time, repeat time (TR), echo time (TE), permutation angle, desired image resolution, dimension and field of view. Wave order is an RF pulse that is used in the atom to be developed to disturb the nuclear position. Once the wave sequence has passed through the patient, the core will fall back to the external magnetic field, and this is always the case, so that the radio-frequency energy can be emitted in a signal manner, which can then be measured by the receiving coil, and finally the desired MRA image can be produced. The relaxation time is the time required for the core to return to the normal position. Various relaxation time modes can be applied, each of which will produce different magnetization characteristics and conditions. Typical relaxation times include: Ti, T2, and T2 *. Finally, the repeat time (TR) is the time interval between the application of each RF pulse, and the echo time (TE) is the excitation pulse and the retransmission wave. -36- This paper size applies the Chinese National Standard (CNS) Α4 specification (210X297 mm) )

裝訂Binding

1221406 A7 B71221406 A7 B7

間之時間，置換角度則是核由币仏罝位移時之角度。應慎選波序參數，以特示出可使血洁另A总名災血及及血管系呈現亮點 (變白）之脈衝序列。對於使血液Tl變短之對比劑（如使血液變白）’這些序列包括以1為主的’擾相梯度回波，或快速梯度回波，但不限於此。在所計劃的一個具體實例中，利用擾相梯度回波序列可得到第二MRI數據組，TR , TE& 轉置角度之選擇依波序而定❶例如，Prince PM 5，417，213)描述用於增亮血液造影之特殊參數。對於因為磁感受性效應使血液變暗之對比劑’如某些以鐵粒子為基礎之作用物，應使用適合的以Τ2*為主之造影策略。精藝者應了解，可使用各種波序變化。在一個具體實例中，標靶MRI對比劑以足以造成固定標乾之Τ !值少於500毫秒之劑量投予。另外，標把MRI對比劑投予之劑量為足以造成固定標靶之T!值少於300毫秒，或少於100亳秒。通常，血管系及固定標靶數據組互相在極短時間内取得。例如，二組數據在單一 MRI段落中取得，其中個體哺乳動物在MRI掃描機中保持相同位置。在一個具體實例中，單次MRI段落可持續低於6小時。另外，單次MRI段落可持續少於4小時，或少於2小時，或少於1小時。再比較第一及第二MRI數據組以決定血管系内固定標靶之存在，限制條件為第二組MRI數據已示出固定標靶之存在。在一個具體實例中，將第一及第二MRI數據組在成像裝置上表現（如並排，或以任一次序依序方式），並具象地本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Time, the replacement angle is the angle when the core is displaced from the coin. The wave sequence parameters should be carefully selected to specifically show the pulse sequences that can make Xie Jie A and the blood and blood vessels show bright spots (whitening). For contrast agents that shorten the blood T1 (such as whitening the blood), these sequences include 1-based spoiled gradient echoes, or fast gradient echoes, but are not limited thereto. In a planned specific example, a second MRI data set can be obtained by using a spoiled gradient echo sequence, and the choice of the TR, TE & transpose angle depends on the wave order. For example, Prince PM 5,417,213) Special parameters for brightening blood angiography. For contrast agents that darken the blood due to magnetic susceptibility effects, such as certain iron particles-based agents, a suitable T2 * -based contrast strategy should be used. The artisan should understand that a variety of wave order variations can be used. In a specific example, the target MRI contrast agent is administered in a dose sufficient to cause a fixed target with a T! Value of less than 500 milliseconds. In addition, the MRI contrast agent is administered in a dose sufficient to cause a T! Value of the fixed target of less than 300 milliseconds, or less than 100 milliseconds. Usually, the vascular system and the fixed target data set are obtained from each other in a very short time. For example, two sets of data are taken in a single MRI segment, where individual mammals remain in the same position on the MRI scanner. In a specific example, a single MRI session can last less than 6 hours. In addition, a single MRI session can last less than 4 hours, or less than 2 hours, or less than 1 hour. The first and second MRI data sets are compared to determine the presence of fixed targets in the vascular system. The limitation is that the second set of MRI data has shown the existence of fixed targets. In a specific example, the first and second MRI data sets are represented on an imaging device (such as side-by-side, or sequentially in either order), and the local paper size is specifically adapted to the Chinese National Standard (CNS) A4 specification 210 X 297 mm)

裝訂Binding

1221406 A7 _ B7 五、發明説明（34 ) 比較。另外，可混合第一及第一 MRI數據組以產生第三MRI數據組，其中包括有固定標靶及血管系之造影。第一及第二 MRI數據組可互相在空間上註明而組合。組合步驟進一步包括將第一或第二]y[RI數據組空間解析插補，如此第一及弟一數據組為相同的空間解析。例如，吾等可決定第一及第二數據組何者有較高之空間解析，並將另一相當之數據組空間解析插補至較南之空間解析。此外，吾等可組合數據組，並將由第一及第二數據組如此註明，插補而來之數據元件個別值組合下之經修飾造影強度直接計算。基於此，經修飾造影強度之直接計算包括將由第一及第二數據組來之經註明且插補數據元件個別數值有變化地加重。第三數據組可示出固定標靶（若有的話）在血管系内之所在。若欲求時，可在成像裝置上呈現第三MRI數據組以示出血管系内固定標靶之所在。第三數據組也可示出血管系内固定標靶之大小及數目。軟體方法可用來將固定標靶及血管系造影一起混合至第三MRI數據組内，其中在單一造影中含有固定標把及血管系。在一個具體實例中，軟體方法進行以下步驟：（丨）第一及第二數據組互相註明，如此二種數據組不會明確註明； (2)若數據組有不同的空間解析，將低解析數據組插補至較高解析數據組之空間解析；（3)生成第三數據組，其為由第一及第二數據組經註明且插補之元件而來之個別數值組合而成之經修飾造影強度之直接估算；及（4)呈現出第三數據 __-38-____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1221406 A7 B7 五、發明説明（35 ) 組以產生固定標靶之單一造影，並相教於血管系造影有大小及外形，及所在位置。組合之造影如此有助於標乾之具象化，可供診斷及進一步之治療介入。進行註明步驟使造影量内之解剖結構對齊，其可能或未必占據分別造影量中之相同區域。當造影絕對地註明時（即病人並未移動且MRI掃描在相同造影段中進行），則為了適切之解剖註明未必需要操作數據量。然而，當病人移動或造影量在不同造影段中取得，則註明是必要的步驟。註明二組數據之特殊方法，依產生第二數據組之方法而定。進行此註明之特殊演算法是文獻中明白示出的且是精藝者所熟知的。在依序採取MR時，利用包含在標準DICOM讀頭内之資料進行單純轉形應已足夠。在其他例子中，可能必須使用商品化之套裝軟體來註明以提供欲求之正確性。類似地’當必須將較低解析度之數據組插補至較高解析數據組之空間解析時，可應用一般可接受的任一種插補演算法。一旦二組數據插補至相同空間解析，其可組合產生第三種數據组，其為第一及第二數據組經註明及插補元件所得之個別數值組合之經修飾造影強度之直接估算。此二數據組可利用演算法組合，如述於U · S ·專利案"磁振血管攝影術數據"，Stefancik et al·，，系列號 09/778,585，公告於 2001年2月7日，以全文列為本案參考，或是可用來將由 MRI機器產生之二造影註明及重疊之其他演算法。除了上述之特殊方法及演算法，有各樣的其他方式可有 _____ -39-_____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）1221406 A7 _ B7 V. Description of the invention (34) Comparison. In addition, the first and first MRI data sets can be mixed to generate a third MRI data set, which includes fixed targets and angiography of the vascular system. The first and second MRI data sets can be spatially annotated and combined with each other. The combining step further includes spatially interpolating the first or second] y [RI data sets, so that the first and younger data sets are the same spatial resolution. For example, we can decide which of the first and second data sets has a higher spatial resolution, and interpolate another comparable data set with a spatial resolution that is more southerly. In addition, we can combine data sets, which will be indicated by the first and second data sets, and the modified contrast intensity under the combination of individual values of the data elements will be directly calculated. Based on this, the direct calculation of the modified contrast intensity includes increasing the individual values of the annotated and interpolated data elements from the first and second data sets with changes. The third data set may show the location of the fixed target, if any, within the vascular system. If desired, a third MRI data set can be presented on the imaging device to show where the target is fixed in the vascular system. The third data set can also show the size and number of fixed targets in the vascular system. The software method can be used to mix the fixed target with the angiography into a third MRI data set, which contains the fixed target and the vascular system in a single angiogram. In a specific example, the software method performs the following steps: (丨) the first and second data sets are marked with each other, so the two data sets will not be clearly marked; (2) if the data sets have different spatial resolutions, the low resolution The data set is interpolated to the spatial analysis of the higher resolution data set; (3) A third data set is generated, which is a combination of individual numerical values from the first and second data sets marked and interpolated components Modify the direct estimation of the intensity of the radiography; and (4) present the third data __- 38 -____ This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1221406 A7 B7 V. Description of the invention (35 ) Group to generate a single radiography of fixed target, and learn the size and shape of the angiography and location. The combined angiography is thus helpful for the visualization of the standard and can be used for diagnosis and further therapeutic intervention. Annotating steps are performed to align the anatomical structures within the contrast volume, which may or may not occupy the same area in the respective contrast volumes. When the imaging is absolutely noted (ie, the patient is not moving and the MRI scan is performed in the same imaging section), the amount of data may not necessarily be manipulated for proper anatomy. However, when the patient moves or the angiographic volume is obtained in different angiographic sections, it is noted that it is a necessary step. The special method for indicating the two data sets depends on the method of generating the second data set. The special algorithms for doing this are clearly shown in the literature and are well known to the artisan. When taking MR sequentially, a simple transformation using the data contained in a standard DICOM readhead should be sufficient. In other examples, it may be necessary to use commercial software packages to indicate this to provide the correctness of the desire. Similarly, when it is necessary to interpolate a lower resolution data set to a spatial resolution of a higher resolution data set, any generally acceptable interpolation algorithm may be applied. Once the two sets of data are interpolated to the same spatial resolution, they can be combined to produce a third type of data set, which is a direct estimate of the modified contrast intensity of the individual numerical combinations of the first and second data sets, annotated and interpolated components. These two data sets can be combined using algorithms, as described in the U.S. patent case " Magneto-Vibratory Angiography Data ", Stefancik et al., Serial number 09 / 778,585, published on February 7, 2001 The full text is used as a reference for this case, or other algorithms that can be used to mark and overlap the two angiography generated by the MRI machine. In addition to the special methods and algorithms mentioned above, there are various other methods available. _____ -39 -_____ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

裝訂Binding

1221406 A7 B7五、發明説明（36 ) 意義地組合數據組，以產生在醫學上有價值之造影。除了並列地單純呈現造影外，其可利用變異最小技術在空間上註明（以作運動之彌補）（如，Woods，R.P·，S.R· Cherry，and J.C. Mazziotta, Rapid Automated Algorithm for Aligning and Reslicing PET Images, Journal of Computer Assisted Tomography，1992，16(4):620-633)，或依據血管系及標靶相共同之基準本質為據而排列。另外，數據組可組合產生包括有血管系及固定標把資料之單一併合造影。此組合係利用灰階（grey-scale)造影，將二造影不同比重下加在一起而進行，例如經分級使固定標靶的亮度約為血管造影的二倍。此變化加重之實例之一是下公式·· 造影（x，y) = a(標把的造影（x，y) + b(血管造影（x，y)) 其中a及b依柱狀圖而自動化選擇，或利用由基礎造影來之標靶選擇而來自動化選擇。另外，數據組之組合可使用色譜以適當地將重疊在血管造影上之固定標靶造影組資料依顏色分碼。可以第三數據組為標竿示出血管系内固定標靶之所在（如在動脈或靜脈内），及就解剖標竿而言之所在，如血管分支點。第三數據組亦可鑑別固定標靶數目，大小及形狀。第三數據組亦可顯示血管系動脈内以固定標靶之精確位置，大小及其形狀。以MRI數據進行之標準實務是以其天然採集之型式總覽數據組’即個別採集部份之平面造影，或利用具象之演算法以將完全的數據量投射至具代表性之二元造影組中。後 •40- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）1221406 A7 B7 V. Description of the invention (36) The data sets are meaningfully combined to produce medically valuable radiography. In addition to simply presenting side-by-side radiography, it can be spatially annotated (to compensate for movement) using minimal variation techniques (eg, Woods, RP ·, SR · Cherry, and JC Mazziotta, Rapid Automated Algorithm for Aligning and Reslicing PET Images , Journal of Computer Assisted Tomography, 1992, 16 (4): 620-633), or according to the nature of the baseline common to the vascular system and target phase. In addition, the data sets can be combined to produce a single merged angiogram including vascular and fixed target data. This combination is performed by using gray-scale angiography, which adds the two contrasts with different specific gravity. For example, the brightness of the fixed target is about twice that of the angiography after classification. One example of this aggravating change is the following formula ... Contrast (x, y) = a (marked contrast (x, y) + b (angiography (x, y)) where a and b are based on the histogram Automatic selection, or automatic selection using target selection from basic angiography. In addition, the combination of data sets can use chromatograms to properly color-code the fixed target angiographic group data superimposed on the angiography by color. The three data sets show the location of fixed targets in the vascular system (such as in arteries or veins), and the location of anatomical targets, such as branch points of blood vessels. The third data set can also identify fixed targets. Number, size, and shape. The third data set can also show the precise position, size, and shape of fixed targets within the vascular arteries. The standard practice with MRI data is to summarize the data set by its natural collection type, that is, individual Collect part of the planar radiography, or use a specific algorithm to project the full amount of data into a representative binary radiography group. Hou • 40- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 Mm)

裝訂Binding

蜂 37 371221406 A7 B7 五、發明説明（ ) 一具象法有二個常用於MRI之主要演算法，最大強度投射 (MIP)及體積重建（volume rendering VR)。這些演算法各自估計數據量所呈現之造影，利用學院派文獻中詳述之方法。這些具象方法在大多數造影總覽工作上常被應用。對於以級數為基礎之造影，如在MRI中常可取得的，所呈現之成像可由這些演算法利用各像素等級來計算。因此所生成之成像主要依賴在MRI數據量内之強度差異。生成組合的數據量（第三數據組）使相關結構間之強度差異由這些演算法可區別，不僅可成像同時可證明討論中之結構。除了對固定標靶之特異親和力，標靶MRI對比劑對於哺乳動物血管系内存在之非固定生物組份也可呈現特異的親和力。在哺乳動物血管系内之非固定生物組份，可為如存在於血管血液匯集内之蛋白質，如人類血清白蛋白，血纖維蛋白原，α -酸性醣蛋白，球蛋白及脂蛋白。參見圖1，示出利用本發明系統及方法以改進血管系内固定標靶具象化之流程。在步驟2 0中，標靶之MRI對比劑投予至疑似因固定標靶所引起之CVD之患者。病人在MRI掃描機内接受標把作用物，如由General Electric，Inc.， Siemens，Philips，Marconi及其他所發展的任何MRI掃描機。也提供可產生三元MRI數據之二元呈現之電腦系統。典型的電腦系統包括 General Electric’s Advantage Windows， Siemens’ 3D Virtuoso，及Syngo，Philips’ Early Vision，Vital Image’s Vitrea，及Algotec’s Provision 0 標靶的對比劑投予至病人後，在步驟2 1可取得第一組數 -41 - 本紙張尺度適用中國國家標準(CMS) A4規格(210X297公釐） 1221406 A7 ____ B7 五、發明説明（38 ) 據，以產生血管系之造影。在第22步驟，取得第二數據組以得固定標乾本身之造影，若其存在時。當固定標乾之對比加強與血液及組織背景比較下在一個可觀察水平時，可採取到第二數據組。在步驟2 3 ’第一及第二數據組在各例中互相註明，其中二個數據組並未明確註明。二數據組註明之特殊方法，依產生第二數據組之方法而定。進行此註明之特殊演算法是文獻中明白告知的，且為精藝者所熟知。在依序M R採集中，利用含於標準DICOM讀頭之資訊進行單純轉形應已足夠。在其他例子中，為提供欲求之正確性，利用商品化套裝軟體進行註明將是必要的。在步驟2 4，若數據組有不同的空間解析，則較低解析數據組可插補至較高解析數據組之空間解析。可應用插補之任何可接受之演算法。在步驟25，第一及第二數據組組合以生成第二數據組，其為第一及第二數據組經修飾造影強度之直接計算。二組數據利用演算法組合，如述於U · S ·專利案，標題為"磁振血管攝影術數據"，Stefancik et al·，系列號No. 09/778,585 ，公告於2001年2月7日，已以全文列為本案參考，或可用於將由MRI機器產生之二個造影註明及重疊之任何其他的演算法。最後，在步驟2 6，產生第三數據組並成像以示出血管系内固定標把之所在。圖1也說明本發明方法另一具體實例，其中在標靶MRI作用物投予後，在某些時間點上對哺乳動物（如病人）投予第 -42- __ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Bee 37 371221406 A7 B7 V. Description of the invention () There are two main algorithms commonly used for MRI in a figurative method, maximum intensity projection (MIP) and volume rendering VR. These algorithms each estimate the contrast presented by the data volume, using methods detailed in academic literature. These figurative methods are often used in most radiographic overview work. For series-based imaging, as is often available in MRI, the rendered imaging can be calculated by these algorithms using each pixel level. Therefore, the imaging generated mainly depends on the intensity difference within the amount of MRI data. The combined data volume (third data set) is generated so that the intensity difference between related structures can be distinguished by these algorithms, which can not only image but also prove the structure in question. In addition to specific affinity for fixed targets, target MRI contrast agents can also exhibit specific affinity for non-fixed biological components present in mammalian vascular systems. Non-fixed biological components in mammalian vascular systems can be proteins such as human serum albumin, fibrinogen, α-acid glycoprotein, globulin, and lipoproteins, such as those present in blood vessel blood pools. Referring to Fig. 1, there is shown a process for improving the visualization of a fixed target in a vascular system using the system and method of the present invention. In step 20, the target's MRI contrast is administered to a patient suspected of having CVD due to the fixed target. The patient receives a target within the MRI scanner, such as any MRI scanner developed by General Electric, Inc., Siemens, Philips, Marconi, and others. Computer systems are also available that can produce binary representations of ternary MRI data. Typical computer systems include General Electric's Advantage Windows, Siemens '3D Virtuoso, and Syngo, Philips' Early Vision, Vital Image's Vitrea, and Algotec's Provision 0 targets. After the contrast agent is administered to the patient, the first step can be obtained in step 21 Number of sets -41-This paper size applies the Chinese National Standard (CMS) A4 specification (210X297 mm) 1221406 A7 ____ B7 V. Description of the invention (38) According to the data, it is used to produce angiography. In step 22, a second data set is obtained to obtain a radiograph of the fixed target itself, if it exists. A second data set can be taken when the comparison of fixed standards is enhanced at an observable level compared with blood and tissue background. In step 2 3 ′, the first and second data sets are indicated in each case, and two of the data sets are not explicitly indicated. The special method indicated in the second data set depends on the method used to generate the second data set. The special algorithms for doing this are clearly known in the literature and are well known to the artisan. In the sequential M R acquisition, a simple transformation using the information contained in a standard DICOM readhead should be sufficient. In other examples, in order to provide the correctness of the desire, it may be necessary to use commercial packaged software to indicate it. In step 24, if the data sets have different spatial resolutions, the lower resolution data sets can be interpolated to the spatial resolution of the higher resolution data sets. Any acceptable algorithm for interpolation can be applied. In step 25, the first and second data sets are combined to generate a second data set, which is a direct calculation of the modified contrast intensity of the first and second data sets. The two sets of data are combined using algorithms, as described in the U.S. patent case, entitled "Magneto-Vibratory Angiography Data", Stefancik et al., Serial No. 09 / 778,585, published in February 2001 On the 7th, the full text has been included as a reference for this case, or any other algorithm that can be used to mark and overlap the two angiography produced by the MRI machine. Finally, at step 26, a third data set is generated and imaged to show where the vascular system fixation marker is located. Fig. 1 also illustrates another specific example of the method of the present invention, in which mammals (such as patients) are administered at a certain time point after the target MRI effector has been administered. CNS) A4 size (210 X 297 mm)

裝訂 1221406 A7 B7 五、發明説明（39 ) 二對比劑（如血管MRI對比劑）。當標靶MRI對比劑之特示劑量本身太低以致無法在血液T丨值上誘生足夠的變化時，則為取得可接受之血管系造影有必要使用此具體實例。標靶MRI對比劑及血管MRI對比劑之用法本發明另一主題是提出在哺乳動物血管系内決定固定標靶存在與否之方法，其中標靶MRI對比劑及血管MRI對比劑投予至哺乳動物，且其中採集血管MRI及標靶MRI數據組。例如，當標靶MRI對比劑之特示劑量太低以致無法在血液T!值上誘生充份之變化而取得可接受之血管系造影（見上文之討論），則額外的對比劑可在標把對比劑之前，之外，可注射之後投予。二種作用物投予之次序可有所變化，並依所選用之對比劑而定。變數包括血管作用物之血中清除率，為標靶對比劑結合之固定標靶比例。若血管對比劑自血中之清除相當慢，而標靶作用物可快速集中，則血管對比劑應可第二個投予。若血管對比劑自血中快速清除，且標靶作用物在相當短時間内集中，則二作用物可同時投予。另外，若標靶作用物需花長時間才集中，則血管對比劑在標靶對比劑注射後才投予。在某些具體實例中，較好在血管系數據取得前先取得相當於標靶數據之數據組，因為對比加強之血管係回復至正常造影（"明亮的”）水平需花較固定標免失去其對比加強所花<時間還長，此乃因存在有標靶對比劑之故。取得血管及標挺數據έ且夕去 ,..,_ 象·，且及時間，依血中標靶對比劑濃本紙張尺度適财關家標準(CNS) Α4規格(21GX297公$-----—- 122I406 A7 ___ B7 五、發明説明（4〇 ) — 度’標乾對比劑滲透至標靶内之速率，及標靶對比劑對標靶親和力而定^取得數據組之時間通常是固定標靶之訊號強度接近其高峰時，或和背景血液及組織相較下對比加強是在可觀察水平之時，或在其最高水平之時。Binding 1221406 A7 B7 V. Description of the invention (39) Two contrast agents (such as vascular MRI contrast agents). This specific example is necessary to obtain acceptable angiography when the specific dose of the target MRI contrast agent is itself too low to induce a sufficient change in the T value of the blood. Use of target MRI contrast agent and vascular MRI contrast agent Another subject of the present invention is to propose a method for determining the presence or absence of a fixed target in a mammalian blood vessel system, in which a target MRI contrast agent and a vascular MRI contrast agent are administered to a breastfeeding Animals, and vascular MRI and target MRI data sets were collected. For example, when the specific dose of the target MRI contrast agent is too low to induce sufficient changes in the T! Value of the blood to obtain acceptable angiography (see discussion above), the additional contrast agent may be It can be administered before, in addition to, or after injection. The order in which the two agents are administered can vary and depends on the contrast agent chosen. Variables include the blood clearance of vascular substrates, which is the ratio of fixed targets bound by the target contrast agent. If the clearance of the vascular contrast agent from the blood is relatively slow and the target can be concentrated quickly, the vascular contrast agent should be administered a second time. If the vascular contrast agent is rapidly cleared from the blood and the target agent is concentrated in a relatively short time, the two agents can be administered simultaneously. In addition, if the target substance takes a long time to concentrate, the vascular contrast agent is administered after the target contrast agent is injected. In some specific examples, it is better to obtain a data set equivalent to the target data before the blood vessel data is obtained, because the contrast-enhanced blood vessels return to the normal angiography (" bright ") level. It takes a long time to lose its contrast enhancement. This is due to the presence of target contrast agents. Obtaining blood vessel and stiffening data, and going away .. ,,, and, depending on the target in the blood, and time Contrast Concentrate Paper Standards (CNS) A4 Specification (21GX297) $ -----—- 122I406 A7 ___ B7 V. Description of the Invention (4〇) — Degree 'standard dry contrast agent penetrates to the target The internal rate and target affinity of the target contrast agent ^ The time to obtain the data set is usually when the signal strength of the fixed target is close to its peak, or when compared with the background blood and tissue, it is at an observable level. At its highest level.

利用波序可採取固定標靶數據組，其中當標靶作用物與之〜。時’可利用固定標把短的T i值。例如，WQ 01/08712揭示利用TR = 36，TE = 5及30。之置換角度之擾相梯度回波序列，以造影出位在兔子頸靜脈内之血栓。若標把作用物以可造成丁2或T2 *縮短之鐵粒子或某些製劑為基礎，則所選用之適合波序是使標靶可過度加強或低度加強。例如，Schmitz et al ·使用3 D小角度快速激發梯度回波序列（TR = 41，TE=11，及置換角度叫5。）以造影出含有 USPIOs之動脈粥樣硬化斑。投予至哺乳動物（如病人）之標靶對比劑劑量，依作用物本身及其對固定標靶之特異親和力，病人的健康史，年齡’體重，性別，遺傳，及身體狀況及其他因素而定，如欲具象化之固定標靶可能的等級，所在及數目。若標靶對比劑對其標把呈現極高之特異親和力，則其可投予相當低之劑量。劑量最終由主治醫師在變化劑量之實驗決定後，由如此中所述般造影而決定。針對血纖維蛋白凝塊而具有親和力之·代表性作用物之建議劑量，述於W0 01/08712，The wave sequence can be used to take a fixed target data set, where the target interacts with it ~. Hour 'can use a fixed index for short T i values. For example, WQ 01/08712 reveals using TR = 36, TE = 5 and 30. The perturbation phase gradient echo sequence of the replacement angle is used to contrast the thrombus in the rabbit jugular vein. If the target is based on iron particles or certain formulations that can cause D2 or T2 * shortening, then the appropriate wave order chosen is to make the target overstrengthened or low-strengthened. For example, Schmitz et al. Used a 3D small-angle fast-excitation gradient echo sequence (TR = 41, TE = 11, and replacement angle called 5.) to image atherosclerotic plaques containing USPIOs. The amount of target contrast agent administered to mammals (such as patients) depends on the agent itself and its specific affinity for the fixed target, the patient's health history, age 'weight, gender, genetics, and physical condition and other factors. Determine the possible level, location and number of fixed targets to be visualized. If the target comparator exhibits a very high specific affinity for its target, it can be administered at a relatively low dose. The final dose is determined by the attending physician after the experiment of varying the dose, and then by the angiography as described above. Suggested doses of affinity and representative agents for fibrin clots are described in WO 01/08712,

其以全文列為本案參考，以具象化血管系中之血栓。在某些具體實例中，標起MRI對比劑投予之劑量應足以造成固定標靶之！^值少於500毫秒。在其他具體實例中，標靶MRI ____ -44- _ __ 本紙張尺度適用中S S家標準(CNS) A4規格(21GX 297公复)~一 ' """" "It is listed in its entirety as a reference to the embodiment of thrombi in the vascular system. In some specific examples, the dose marked with MRI contrast agent administration should be sufficient to cause a fixed target! ^ Value is less than 500 ms. In other specific examples, the target MRI ____ -44- _ __ This paper standard is applicable to the SS Home Standard (CNS) A4 specification (21GX 297 public copy) ~ one '" " " " "

裝訂Binding

12214061221406

對比劑投予之劑量應足以使固定標靶之τ!值少於3〇〇毫秒，或少於100毫秒。在血管系内之固定標靶可以是組織，生物結構，細胞，細胞表面，或生物聚合物。在其中固定標靶是生物結構之具體實例中，生物結構可以是與CVD有關之結構，如血栓，動脈粥樣硬化斑，動脈粥樣硬化傷害，腫瘤，或血栓插栓。另外，固定標靶可以是生物聚合物。與(:¥以有關之生物聚合物實例有：脂質，脂蛋白，蛋白質，多肽及多醣。若固定標靶是生物聚合物，生物聚合物通常是以高濃度存在於CVDs内之蛋白質，如血纖維蛋白及膠原蛋白。如上述，方法中包括對哺乳動物投予標靶之MRI對比劑。標挺的對比劑對固定標靶具有特異親和力，且標靶的對比劑可提供固定標靶對比加強。標靶的MRI對比劑對於固定標把具有特異親和力。在某些具體實例中，標靶mri 對比劑之特異親和力，以解離常數表示，少於5〇。在其他具體實例中，特異親和力少於5iC/]VI。又在其他具體實例中，特異親和力是少於〇 5 #Μ。可用於此中所揭示之本發明方法中充作標靶對比劑之建議化合物或組合物為於W〇 01/08712中所鑑知之對比劑，以全文列為本案參考，及於U s臨時案，，以肽-為基礎之多元標靶的·對比劑丨’Zhang et al·，，受讓予EPIX Medical Inc·，公告於200 1 年7 月 30 日，U.S. Ser. No. 60/308,721 及在，，以肽-為基礎之多元標把對比劑"，Zhang et al·，，受讓予EPIX Medical Inc·且與之同時公告，u.S. Ser· No·_，二者均 ------ -奶- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公I)The dose of the contrast agent should be sufficient to make the τ! Value of the fixed target less than 300 milliseconds, or less than 100 milliseconds. Fixed targets within the vascular system can be tissues, biological structures, cells, cell surfaces, or biopolymers. In a specific example where the fixed target is a biological structure, the biological structure may be a structure related to CVD, such as a thrombus, an atherosclerotic plaque, an atherosclerotic injury, a tumor, or a thrombus plug. In addition, the fixed target may be a biopolymer. Examples of biopolymers related to (: ¥ include: lipids, lipoproteins, proteins, peptides, and polysaccharides. If the fixed target is a biopolymer, the biopolymer is usually a high concentration of proteins such as blood in CVDs. Fibrin and collagen. As described above, the method includes administering an MRI contrast agent to the target in the mammal. The stiff contrast agent has specific affinity for the fixed target, and the target's contrast agent can provide fixed target contrast enhancement. The target MRI contrast agent has specific affinity for fixed targets. In some specific examples, the specific affinity of the target mri contrast agent is expressed as a dissociation constant, less than 50. In other specific examples, the specific affinity is low In 5iC /] VI. In other specific examples, the specific affinity is less than 0.05 #M. The suggested compound or composition that can be used as the target contrast agent in the method of the present invention disclosed herein is The contrast agents known in 01/08712 are listed in their entirety for reference, and in the US Provisional Case, peptide-based multi-target targets · Contrast agents 丨 Zhang et al ·, Assignee EPIX Medical Inc., Announced July 30, 2001, US Ser. No. 60 / 308,721 and In, Peptide-Based Multiple Standards Contrast Agent ", Zhang et al., Assigned EPIX Medical Inc · and announced at the same time, uS Ser · No · _, both ------ -milk-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 male I)

裝 1221406 A71221406 A7

五、發明説明（42 ) 以全文列為本案參考。可用於本發明之其他標靶對比劑包括血纖維蛋白標靶之對比劑，如Lanza et al··，Acad· Radiol· 5 (suppl.l) ·· S173- S176 (1998)所述，及 Yu et al·，Magnetic Resonance i11 Medicine 44:867-872 (2000) ; Johansson et al·，的血小板樣靶粒子，J. Meg· Res. Imaging 13: 615-618 (2001) ; Sipkins et al ·，的a v冷3整合素標乾作用物，Nature Medicine 4(5): 623-626 (1998) ; Sipkins et al·，的 ICAM-1 標靶作用物 ’ J· Neuroimmunol. 104: 1·9 (2000) ; Moore et al·，所述之針對斑或感染之巨噬細胞標靶，JMRI 7:1140-1145 (1997);如 Weissleder et al.，所述之針對心肌梗塞之抗-肌凝蛋白作用物，Radiology 181: 245-249 (1991) ; Kornguth et al·，的淋巴細胞特異作用物，J. Neurosurg. 66: 8980906 (1987); Schmitz et al ·，的斑標乾作用物，Investigative Radiology 35 (8): 460-471 (2000);及 Ruehm et al·，之斑標靶作用物， Circulation: 415-422(2001年6月23日），以上均以全文列為本案參考。可用於本發明方法之標靶的MRI對比劑特殊實例包括： -46- 本紙張尺度適用中國國家棣準(CNS) A4規格(210 X 297公釐)V. Description of Invention (42) The full text is incorporated as a reference in this case. Other target contrast agents that can be used in the present invention include contrast agents for fibrin targets, as described in Lanza et al · ·, Acad · Radiol · 5 (suppl.l) ·· S173-S176 (1998), and Yu et al., Magnetic Resonance i11 Medicine 44: 867-872 (2000); Johansson et al., Platelet-like target particles, J. Meg · Res. Imaging 13: 615-618 (2001); Sipkins et al., Av Cold 3 Integrin Standard Stem Substance, Nature Medicine 4 (5): 623-626 (1998); Sipkins et al., ICAM-1 Target Substance 'J. Neuroimmunol. 104: 1 · 9 (2000) Moore et al., Described plaque or infected macrophage targets, JMRI 7: 1140-1145 (1997); as described by Weissleder et al., Anti-myosin agents against myocardial infarction , Radiology 181: 245-249 (1991); Kornguth et al., Lymphocyte Specific Actuators, J. Neurosurg. 66: 8980906 (1987); Schmitz et al., Spotted Stem Actors, Investigative Radiology 35 ( 8): 460-471 (2000); and Ruehm et al., Spot Targets, Circulation: 415-422 (June 23, 2001), all of which are listed in full text Reference case. Specific examples of MRI contrast agents that can be used as targets for the methods of the present invention include: -46- This paper size applies to China National Standards (CNS) A4 (210 X 297 mm)

裝訂Binding

1221406 A71221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1221406 A7B7This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1221406 A7B7

本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1221406 A7 B7 五、發明説明（47 ) 及結構IX :This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) 1221406 A7 B7 V. Description of invention (47) and structure IX:

〇依據本案方法，也將血管MRI對比劑投予哺乳動物。其可對哺乳動物提供血管系對比之加強作用。原則上，適合之血管系MRI對比劑除了目前已商品化或在臨床上已發展的，包括有細胞外對比劑，氧化鐵粒子對比劑（例如 USPIOs及MIONs)，及血液匯集對比劑。一般而言，對比劑均含有釓（III)，此乃因在造影所需之大劑量下，釓仍是無毒的，參見"Gadolinium (III) Chelates as MRI Contrast Agents : Structure, Dynamic, and Applications, ”P· Caravan et al· Chem. Rev. 99· 2293-2352 (1999)，其以全文列為參考。血管]VHII對比劑之劑量為在投藥後足以使血中T丨值少於 300毫秒者。另外其劑量可使Τϊ值少於175或少於100毫秒。可用於本發明方法中某些細胞外對比劑實例包括精藝者 __ -51-_ 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐） 1221406 A7 B7 五、發明説明（48 ) 已知之作用物，如 ProHanceTM(Bracco SpA)及 Magnevist (Schedng AG)。可用於本發明的細胞外MRI對比劑某些結構包括： o2c~x 厂厂co2·〇 In accordance with the method of this case, a vascular contrast agent is also administered to mammals. It can provide enhanced vascular contrast in mammals. In principle, suitable MRI contrast agents for blood vessels are currently commercially available or clinically developed, including extracellular contrast agents, iron oxide particle contrast agents (such as USPIOs and MIONs), and blood pooling contrast agents. Generally speaking, contrast agents contain thallium (III), because thorium is still non-toxic at the large doses required for imaging, see " Gadolinium (III) Chelates as MRI Contrast Agents: Structure, Dynamic, and Applications , "Caravan et al. Chem. Rev. 99 · 2293-2352 (1999), which is incorporated by reference in its entirety. Vascular] The dose of VHII contrast agent is sufficient to give a blood T value of less than 300 milliseconds after administration. In addition, its dosage can make the TQ value less than 175 or less than 100 milliseconds. Some examples of extracellular contrast agents that can be used in the method of the present invention include Jingyi __ -51-_ This paper size applies to Chinese national standards (CNS ) A4 size (210 X 297 mm) 1221406 A7 B7 V. Description of the invention (48) Known agents, such as ProHanceTM (Bracco SpA) and Magnevist (Schedng AG). Some of the extracellular MRI contrast agents that can be used in the present invention The structure includes: o2c ~ x factory factory co2 ·

.N N N < Gd3+ 〉 C〇2 C(V (Gd-DTPA), C〇2 /—C02· ,N N..N N N < Gd3 +〉 Co2C (V (Gd-DTPA), Co2 /-C02,, N N.

Gd3+ ：N N〆 *o2c- c〇2· (Gd-DOTA)， C02· CH3NHOC—\ ~φ~^ /—CONHCH3 N N 广 Gd3+ )c〇2· C02- (Gd-DTPA-BMA)， CO, 裝訂 o2c-Gd3 +: NN〆 * o2c- c〇2 · (Gd-DOTA), C02 · CH3NHOC— \ ~ φ ~ ^ / —CONHCH3 NN guang Gd3 +) c02 · C02- (Gd-DTPA-BMA), CO, binding o2c-

N N； Gd3+〕〇H ；N .CH3 c〇2" (Gd-HP-D03A), C02· CH3OCH2CH2NHOC—X /~\(/~\ /—CONHCH2CH2OCH3 N N Nv (Gd3+ ^ C02* C〇2* (gadoversetamide)，及 -52- 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐） 1221406 A7 B7 五、發明説明（49 )NN; Gd3 +] 〇H; N .CH3 c〇2 " (Gd-HP-D03A), C02 · CH3OCH2CH2NHOC—X / ~ \ (/ ~ \ / —CONHCH2CH2OCH3 NN Nv (Gd3 + ^ C02 * C〇2 * (gadoversetamide ), And -52- This paper size applies to China National Standard (CNS) A4 (210x 297 mm) 1221406 A7 B7 V. Description of the invention (49)

(gadobutol). 雖然通常包括以釓為基礎之作用物，氧化鐵粒子對比劑也可用來加強（經由負面對比）血管系。此作用物包括氧化鐵之超小粒子（USPIOs)，或單晶體氧化鐵粒子（MIONs)。這些作用物為氧化鐵粒子為内質網系（RES)及單核吞噬細胞系（MPS )，所吸收，造成在肝，脾，肺及在巨噬細胞活性區域，如動脈粥樣硬化傷害，中之分佈。實例包括作用物 FerridexTM( Advanced Magnetics，Inc·)。關於本發明方法中可用之血液匯集對比劑，實例包括市售的或在發展或臨床試驗的，包括MultiHanceTM (Bracco SpA) ； MS-325 (EPIX Medical Inc.) ； Eovist™(Schering AG)，及揭示於 US Pat. 5,798,092 及 5,695,739 及 5,733,528 之對比劑。應注意，血液匯集是有大總體積之可移動組織，如約3升血漿量或成人中。血液匯集也經由其他器官過滤，如肝，腎，脾I肺，可影響其體積及分佈，以及在這些器官中可被造影之血管之大小。雖然細胞外及血液匯集對比劑可在整個血管空間中分佈，但無一者可直接造影出哺乳動物血管系内之固定標靶，且通常對固定標靶不呈現特異的親和 -53- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1221406 A7 B7 五、發明説明（5〇 ) 力。關於”血液匯集"MRI對比劑之一般資料，見"Blood Pool Contrast Agents for Cardiovascular MR Imaging” by L.J.M· Kroft et al· JMRI 10，395-403 (1999)，已列入本案參考，及"The Future of Contrast-Enhanced Magnetic Resonance Angiography: Are Blood Pool Agents Needed?" by A. Muhler Invest· Radiol. 33, 709-714 (1998)，也列為本案參考。可用於本發明之血液匯集對比劑之其他實例包括：MP-2269(Mallinckrodt，Inc·)及揭示於 US Pat. 5,888,576 之對比劑；揭示於PCT案No. WO 95/28179及WO 96/23526之對比劑，已全文列為本案參考；P760(Geurbet) ; Gadomer-17TM (Schering AG)及揭示於 US Pat. 5,876,698 ; 5,820,849 ; 5,681,543 ; 5,650，136 及 5,364,614 之對比劑；ClariscanTM (Nycomed Amersham)及揭示於 PCT 案 WO 96/09840 及 WO 9725073 之對比劑；及 B22956/l(Bracco SpA)及揭示於 PCT 案 WO 00/30688，WO 98/05625，WO 98/05626，WO 95/32741 ，WO 98/38738，WO 95/32741 及 US Pat. 5,649,537。特言之，可用於本發明之某些血液匯集對比劑之結構包括： ____-54- 本紙張尺度適用中國國家棣準(CNS) A4規格(210X 297公釐)(gadobutol). Although thorium-based agents are often included, iron oxide particle contrast agents can also be used to strengthen (via negative contrast) the vascular system. This substrate includes ultra-small particles of iron oxide (USPIOs), or single crystal iron oxide particles (MIONs). These agents are absorbed by the iron oxide particles of the endoplasmic reticulum system (RES) and the mononuclear phagocytic cell line (MPS), causing damage to the liver, spleen, lung and active areas of macrophages, such as atherosclerosis, In the distribution. Examples include the agent FerridexTM (Advanced Magnetics, Inc.). Concerning blood pooling contrast agents that can be used in the method of the present invention, examples include those commercially available or under development or clinical trials, including MultiHanceTM (Bracco SpA); MS-325 (EPIX Medical Inc.); Eovist ™ (Schering AG), and Contrast agents disclosed in US Pat. 5,798,092 and 5,695,739 and 5,733,528. It should be noted that blood pooling is mobile tissue with a large total volume, such as about 3 liters of plasma volume or in adults. Blood pooling is also filtered by other organs, such as liver, kidney, spleen, and lung, which can affect its volume and distribution, and the size of blood vessels that can be imaged in these organs. Although extracellular and blood pooling contrast agents can be distributed throughout the vascular space, none of them can directly image fixed targets in mammalian vascular systems, and usually do not show a specific affinity for fixed targets. -53- The scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1221406 A7 B7 V. Description of invention (50). For general information on "blood pooling" MRI contrast agents, see "Blood Pool Contrast Agents for Cardiovascular MR Imaging" by LJM · Kroft et al · JMRI 10, 395-403 (1999), which has been included in this case for reference, and " ; The Future of Contrast-Enhanced Magnetic Resonance Angiography: Are Blood Pool Agents Needed? &Quot; by A. Muhler Invest · Radiol. 33, 709-714 (1998), which is also included as a reference for this case. Other examples of blood pooling contrast agents that can be used in the present invention include: MP-2269 (Mallinckrodt, Inc.) and contrast agents disclosed in US Pat. 5,888,576; disclosed in PCT Case Nos. WO 95/28179 and WO 96/23526 Contrast agents, which are listed in their entirety as references; P760 (Geurbet); Gadomer-17TM (Schering AG) and contrast agents disclosed in US Pat. 5,876,698; 5,820,849; 5,681,543; 5,650,136 and 5,364,614; ClariscanTM (Nycomed Amersham) and disclosure Contrast agents in PCT cases WO 96/09840 and WO 9725073; and B22956 / 1 (Bracco SpA) and disclosed in PCT cases WO 00/30688, WO 98/05625, WO 98/05626, WO 95/32741, WO 98 / 38738, WO 95/32741 and US Pat. 5,649,537. In particular, the structures of certain blood pooling contrast agents that can be used in the present invention include: ____- 54- This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm)

裝訂Binding

1221406 A71221406 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1221406 Α7This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1221406 Α7

-02C-02C

02*02 *

-〇2C-〇2C

-〇2〇(B-22956/1). 、co? —血管MRI對比劑也可對存在於哺乳動物血管系内之非固疋生物組份呈現特異的親和力。存在於哺乳動物血管系内之非固定之生物組份之實例，包括存在於血液及血液血清内义蛋白質，如人類血清白蛋白，血纖維蛋白原，以·酸性膽蛋白，球蛋白，及脂蛋白。血管MRI作用物之劑量可受注射方法及作用物自血液匯集中之清·除率而影響。例如，快速濃注（其經歷時間後單一注射可分佈全部血液匯集），或在短時間下快速注射，通常可造成血管對比劑之血液濃度呈雙-指數衰退降低。因為Τι 或T 2變化是對比劑濃度之函數關係，τ 1或T 2之大變化當對 -56- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐） 1221406 A7 B7-〇2〇 (B-22956 / 1)., Co?-Vascular MRI contrast agent can also show specific affinity for non-solid biologic components existing in the mammalian vascular system. Examples of non-fixed biological components present in mammalian blood vessels include blood and blood serum endogenous proteins such as human serum albumin, fibrinogen, acidic choline, globulin, and lipids protein. The dose of vascular MRI effector can be affected by the injection method and the clearance and removal rate of the effector from the blood pool. For example, rapid bolus injection (which distributes the entire blood pool after a single injection) or rapid injection in a short period of time usually results in a bi-exponential decrease in blood concentration of the vascular contrast agent. Because the change in Ti or T 2 is a function of the concentration of the contrast agent, a large change in τ 1 or T 2 should be correct. -56- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1221406 A7 B7

比劑最高濃度時可造成對比劑大程度變化。結果，當血液濃度高且清除率最低時，造影血液匯集之合宜時間（及因此之血管系統）是投予血管MRI作用物後立即進行。例如，於 •’動態”對比MRA時，造影係在經設計以造影血液薩集之對比劑，如M S - 325，快速濃注後立即進行。一般而言，標靶MRI對比劑投予之劑量為由約〇〇〇1至約 500微莫耳/公斤，且血管MRI對比劑投予之劑量為由約1〇至約300微莫耳/公斤。在其他具體實例中，標乾μ ri對比劑投予之劑量為約0.001至約50微莫耳/公斤，且血管MRI 對比劑投予之劑量為由約5至約3 0微莫耳/公斤。另外，標靶MRI對比劑投予之劑量為由約〇·〇〇 1至約5微莫耳/公斤，且血管MRI對比劑投予之劑量為由約〇·〇〇 1至約3微莫耳/公斤。在方法中，採取含有血管系造影之血管MRI數據組及標靶MRI數據組。標靶數據組取得之時間為適於提供固定標靶對比加強之可觀察水平時，此係相較於背景血液及組織加強而言。在某些具體實例中，標靶MRI數據利用擾相梯度回波序列採取。在一個具體實例中，標靶對比劑在血管對比劑之前投予，且標靶MRI數據組在血管MRI數據組之前採取。另外，標洛對比劑及血管對比劑可同時投予，且血管MRI數據在標靶MRI數據組之前採取。當哺乳動物（如病人）保持在MRI機器中時，標靶及血管數據組可在單一 MRI段落中採取。 -57- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)The highest concentration of the specific agent can cause a large change in the contrast agent. As a result, when blood concentrations are high and clearance is minimal, the appropriate time for angiographic blood pooling (and therefore the vascular system) is performed immediately after administration of a vascular MRI agent. For example, in “dynamic” contrast MRA, the contrast is designed to be contrasted with blood saset, such as MS-325, immediately after the rapid injection. Generally speaking, the target MRI contrast agent dose Is from about 0.001 to about 500 micromoles / kg, and the vascular contrast agent is administered at a dose of from about 10 to about 300 micromoles / kg. In other specific examples, the standard μ ri contrast The dose of the agent is about 0.001 to about 50 micromoles / kg, and the dose of the vascular MRI contrast agent is about 5 to about 30 micromoles / kg. In addition, the target MRI contrast agent is administered The dose is from about 0.001 to about 5 micromoles / kg, and the vascular contrast agent is administered from about 0.001 to about 3 micromoles / kg. In the method, it is taken to contain Angiographic angiographic MRI data set and target MRI data set. When the target data set is obtained at an observable level suitable for providing fixed target contrast enhancement, this is compared to background blood and tissue enhancement. In some specific examples, target MRI data is taken using spoiled gradient echo sequences. In a specific example, the target contrast agent is administered before the vascular contrast agent, and the target MRI data set is taken before the vascular MRI data set. In addition, the standard Luo contrast agent and the vascular contrast agent can be administered simultaneously, and the vascular MRI data is The target MRI data set was taken before. When mammals (such as patients) are kept in the MRI machine, the target and vascular data sets can be taken in a single MRI segment. -57- This paper size applies Chinese National Standard (CNS) A4 Specifications (210X 297 mm)

裝訂Binding

1221406 A7 B7 五、發明説明（54 ) 標把對比劑及血管對比劑互相可在2小時内投予。另外，標靶對比劑及血管對比劑可互相在3 〇分鐘内投予，或互相在1 5分鐘内投予。血管mri對比劑可以快速濃注或輸液方式投予。若採輸液方式，可使用少於丨5分鐘之輸液時間。在其他具體實例中，可使用少於丨〇分鐘或少於3分鐘之輸液時間。血管及標靶MRI數據組可互相比較以決定血管系内固定標把之存在，限制條件為標靶MRI數據組可示出固定標起之存在。血管及標把MRI數據組也可組合《例如，血管及標靶MRI數據組可組合產生第三MRI數據組，其包括固定標乾及血管系之造影。第三數據組也可示出固定標靶（若存在時）之所在及大小（及血管系内）。若欲求時，第三Mpj數據組也可在成像裝置上表現，以示出血管系内固定標乾（若存在時）之所在及大小。數據組可互相在空間上註明標靶及血管MRI數據組而組合。組合步驟也包括將血管或標靶MRI數據組任一者之空間解析插補，使二者有相當之空間解析。例如，在一個具體實例中，吾等可決定血管或標靶MRI數據組何者有較高之空間解析；再將相當的另一數據組之空間解析插補至較高空間解析。另外，組合步驟包括經修飾造影強度之直接估計，其^始自由如此註明，插補之血管及標靶MRI數據組數據元件而來之個別的數值之組合^在一個具體實例中，經修飾造影強度之直接計算包括，將來自血管及標靶MRI 數據組之註明的，插補的數據元件個別數值之變化加重。 -58- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)1221406 A7 B7 V. Description of the Invention (54) The standard contrast agent and vascular contrast agent can be administered to each other within 2 hours. In addition, the target contrast agent and the vascular contrast agent may be administered within 30 minutes of each other, or within 15 minutes of each other. The vascular mri contrast agent can be administered by rapid infusion or infusion. If the infusion method is used, an infusion time of less than 5 minutes can be used. In other specific examples, an infusion time of less than 10 minutes or less than 3 minutes can be used. The vascular and target MRI data sets can be compared with each other to determine the presence of fixed markers in the vascular system. The limitation is that the target MRI data set can show the presence of fixed markers. The vascular and target MRI data sets can also be combined. For example, the vascular and target MRI data sets can be combined to produce a third MRI data set, which includes fixed standard stem and vascular system radiography. The third data set can also show the location and size (and within the vascular system) of the fixed target (if present). If desired, the third Mpj data set can also be represented on the imaging device to show the location and size of the anchorage (if any) within the vascular system. The data sets can be spatially marked with target and vascular MRI data sets. The combining step also includes spatially interpolating either the blood vessel or the target MRI data set, so that the two have comparable spatial resolution. For example, in a specific example, we can determine which of the vascular or target MRI data sets has a higher spatial resolution; then interpolate the spatial resolution of a comparable other data set to a higher spatial resolution. In addition, the combination step includes a direct estimation of the intensity of the modified angiography, which is indicated freely, the combination of the individual values from the data elements of the intervening blood vessel and the target MRI data set ^ In a specific example, the modified angiography The direct calculation of the intensity includes aggravating the changes in the individual values of the interpolated data elements as noted from the vascular and target MRI data sets. -58- This paper size applies to China National Standard (CNS) A4 (210X 297mm)

裝 ijIj

1221406 A7 B7 五、發明説明（551221406 A7 B7 V. Description of the invention (55

數壚之成像以MR數據進行之標準實務是總覽其在天然採取型式下之數據組，即個別採取切片之平面造影，或可利用具象化演算法，以將整個數據量投射至具代表性之二元造影組中。具象化之後一方法有二個常用於MRI的主要方法，最大強度投射（MIP)及體積重建（v〇iume ren(jering vr)。這些演算法各自估計教據量所呈現之造影，利用學院派文獻中詳述之方法。這些具象方法在多數造影總覽工作上常被應用。對於以級數為基礎之造影，如在MRI中常可取得的，所呈現之成像可由這些演算法利用各種像素等級來計算，因生成組合之數據量（第三數據組）使相關結構間之強度差異由這些演算法可區分，不僅成像並同時證明其結構。特別地，成像模式的一個實例是標準的灰階MIP ,其中固定標靶有最高之總體強度，血管系為中度總體強度，而周圍組織具較低之總體強度。此途徑之延伸可為對特異強度帶加上色彩編碼，令結構可依賴顏色及強度而區分，或限於其顏色，相對於在灰階MIP中之強度差異。另一成像方法是數據之VR陳述，其具有最高強度之固定標靶，具中度總體強度之血管系，及具較低總體強度之周園組織。在 VR陳述上之排列包括針對不同的具象化作用及/或特異強度帶α頻·道（不透光）之控制，某些或所有強度區域之色彩編碼。控制色彩及/或α為一般的VR指示，且為精藝者所熟知。數據組成像的第三個實例是影像擴取片之平面具象化。 •59- 本纸張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1221406 A7 _____Β7 五、發明説明（56 ) 在此例中’所成像之造影是代表所擷取解剖區域之影像序列❶組合影像之強度再次針對欲具象化之各主要結構分成高’中及低強度。色彩編碼及/或對比/強度操作可提供成像造影結果不同之具體實例。成像所輸出之數據的第四例已知為多層面重組（MPR)。 MPR通常以平面型式成像所顯影之數據；然而所具象區域之厚度，方位及間距及組合組份像素成為所輸出之造影之方法均可變化^ MPR可利用上列之強度差異及色彩編碼提供有固定標靶組份，血管系組份及周圍組織之影像，且有可區別之色彩及/或強度，其方式和先前三實例所列的高度類似。實例童·例:血管劑繼之標靶劑用法之活體内策略利用血管劑（如細胞外對比劑或血液匯集作用物）及標靶對比劑，於活體内顯影血管系内之固定標靶（如血栓）的一種步驟如下：將600克天竺鼠（Hartley雄的）麻醉。切開喉部’並分出一條頸靜脈。以血管夾分出一段1公分的頸靜脈。新鮮抽出之血液（50微升）混合以人類凝血酶（5〇微升，4單位）再注入靜脈已夾住之段落。注射後4分鐘，移開夾子’且血栓熟化30分鐘。注入GdDTPA(Magnevist®)， 100微莫—耳/公斤，一種細胞外對比劑，再利用在GE Medical Systems上之下列波序顯影出天竺鼠之喉部區域： 1·5Τ MRI : T 1 -加重之 SPGR，TE = 3.1，TR = 22，置換角The standard practice of digital imaging using MR data is to summarize its data set in the natural adopting type, that is, to take plane imaging of slices individually, or use a visualization algorithm to project the entire data volume to a representative In the binary radiography group. After the visualization, there are two main methods commonly used in MRI, maximum intensity projection (MIP) and volume reconstruction (v〇iume ren (jering vr). These algorithms each estimate the amount of contrast presented by the evidence, using the academic method The methods detailed in the literature. These figurative methods are often used in most imaging overview work. For series-based imaging, as is often available in MRI, the imaging presented can be performed by these algorithms using various pixel levels. It is calculated that the intensity difference between related structures can be distinguished by these algorithms due to the amount of generated data (third data set), not only imaging but also proving its structure. In particular, an example of the imaging mode is the standard gray-scale MIP Among them, the fixed target has the highest overall intensity, the vascular system has a moderate overall intensity, and the surrounding tissues have a lower overall intensity. This approach can be extended by adding color coding to specific intensity bands, so that the structure can rely on color and The intensity is distinguished, or its color is limited, compared to the intensity difference in the gray-scale MIP. Another imaging method is the VR statement of the data, which has Highest-intensity fixed targets, vascular systems with moderate overall strength, and peripheral tissues with lower overall strength. Arrangements on VR statements include targeting specific figurative effects and / or specific intensity bands with alpha frequencies. (Opacity) control, color coding of some or all intensity areas. Control color and / or α are general VR indicators and are well known to artisans. A third example of a data composition image is image expansion The plane of the film is figurative. 59- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1221406 A7 _____ Β7 5. Description of the invention (56) In this example, 'the imaged imaging is representative The captured image sequence of the anatomical area and the intensity of the combined image are again divided into high, medium, and low intensities for each major structure to be embodied. Color coding and / or contrast / intensity operations can provide specific examples of different imaging contrast results. Imaging The fourth example of the output data is known as multi-layer reconstruction (MPR). MPR is usually developed by imaging in a flat pattern; however, the thickness, orientation, spacing, and composition of the imaged area The method of changing the pixels into the output angiography can be changed. ^ MPR can use the intensity differences and color coding listed above to provide images of fixed target components, vascular system components and surrounding tissues with distinguishable colors and / or Intensity, in a manner similar to the heights listed in the previous three examples. Example Child · Example: In-vivo strategy of vascular agent followed by target agent use of vascular agent (such as extracellular contrast agent or blood pooling agent) and target comparison Agent in vivo to develop a fixed target (such as a thrombus) in a vascular system as follows: Anesthetize 600 grams of guinea pigs (Hartley male). Cut the throat 'and divide a jugular vein. Use a vascular clip to divide a section 1 cm jugular vein. Freshly drawn blood (50 microliters) is mixed with human thrombin (50 microliters, 4 units) and injected into the vein clamped section. 4 minutes after injection, the clip 'was removed and the thrombus was matured for 30 minutes. Inject GdDTPA (Magnevist®), 100 μM-ear / kg, an extracellular contrast agent, and then use the following wave sequence on GE Medical Systems to develop the larynx area of guinea pigs: 1.5T MRI: T 1-Aggravated SPGR, TE = 3.1, TR = 22, replacement angle

度= 40° 。（另外，注入血液匯集對比劑）。在注入（jdDTPA _____-60- 本紙張尺度適种s s家標準(CNS) A4規格(21G X 297公爱)~ " 1221406 A7 B7 五、發明説明（57 ) 後’ 管系統立即有某些加強作用，在注入GdDTpa後血栓則並未加強。3 0分鐘後，GdDTPA自血中清除，再注入劑量6微莫耳/公斤之固定標靶（血栓）標靶MRI作用物。和血液及血管系比較，血栓似乎較明亮，且此亮色成像到注入標靶作用物後6 0分鐘會隨時間而褪色。數據，暗地裏註明的’予以組合並利用Algotec Provision工作站具象之，以示出血管系内加強之血栓所在，如下·· -利用Archives Manager，選出血管顯影系列，再來是固定標靶顯影系列，分別是系列1及系列2。 •在”處理M手冊中，選擇’組合顯影，。 •在自動手冊中，選擇2為f影像組合，。 •在自動手冊中，針對系列1及2輸入適合數值。 •進行顯影組合，並將顯影保留在欲求所在。发使用標靶MRI對比劑以顯影血管系及固定標乾之活體内策略以血栓-標靶對比劑於活體内顯影血管系及固定標乾之步驟如下：將600克之天竺鼠（Hartley雄的）麻醉。在喉部切開，並分離出一條頸靜脈。以血管夾分出丨公分的頸靜脈段落。新鮮抽出之血液（5 0微升）混合以人類凝血酶（5〇微升’ 4單位）並注入靜脈已夾住之段落中。注射後4分鐘，移開夾子，-血栓熟化3 0分鐘。將此中所述之血栓_標靶對比劑 (10微莫耳/公斤’ 40微莫耳Gd /公斤）經由導管輸送至頸動脈’動物再於GE Medical System 1.5特斯拉mri下，利用下列波序顯影：IV加重之SPGR，丁丑=3.1，丁11 = 22，置換 1 _-61 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝訂Degree = 40 °. (Also, blood is injected to pool the contrast). After injecting (jdDTPA _____- 60- this paper size is suitable for ss home standard (CNS) A4 specification (21G X 297 public love) ~ " 1221406 A7 B7 V. Description of the invention (57) immediately after the tube system has some strengthening After 30 minutes, GdDTPA was cleared from the blood, and a fixed target (thrombus) target MRI agent at a dose of 6 μmol / kg was injected. And blood and blood vessels In comparison, the thrombus appears to be brighter, and this bright color will fade over time 60 minutes after being injected into the target. Data, implicitly marked 'combined and visualized with Algotec Provision workstation to show intravascular enhancement The location of the thrombus is as follows--Use the Archives Manager to select the angiography series, and then the fixed target development series, which are series 1 and series 2. • In the "Processing M Manual, select 'Combined Development.' In the manual, select 2 as the f-image combination. • In the manual, enter the appropriate values for series 1 and 2. • Perform the development combination and keep the development where you want it. MRI contrast agent in vivo strategy to develop blood vessels and fixed standard. The procedure of thrombus-target contrast agent in vivo to develop blood vessels and fixed standard is as follows: 600 grams of guinea pigs (Hartley male) are anesthetized. In the throat Incision and separation of a jugular vein. Jugular vein segments separated by vascular clamps. Freshly drawn blood (50 microliters) was mixed with human thrombin (50 microliters' 4 units) and injected into the vein. Stay in the paragraph. 4 minutes after the injection, remove the clip,-30 minutes for the thrombus to mature. The thrombus_target contrast agent described in this (10 μmol / kg '40 μmol Gd / kg) The catheter was delivered to the carotid artery and the animals were developed under GE Medical System 1.5 Tesla mri using the following wave order: SPGR with IV aggravation, Ding Chou = 3.1, Ding 11 = 22, Replacement 1 _-61-This paper applies to the standard China National Standard (CNS) A4 (210 X 297 mm) binding

赛 1221406 A7 _____B7 五、發明説明（58 ) 角度=2 7° 。最***液訊號似乎較血栓為明亮，隨著時間變化’血液訊號漸衰退而血栓訊號強度仍持續著，如此和血液比較下血栓變得較為明亮。由早先之血管系數據加上後來揭取之數據，顯示血栓有被加強。將背地裏註明之數據再予以組合，利用Algotec Provision工作站具象化，以示出血管系内被加強影像之血栓之所在，方法如上述。實例3 :在血管系中分析訊號強度及固定標靶上單獨使用標靶作用物圖2A證明，當標靶對比劑用來顯影血管系及固定標靶時’相對於時間下在固定標靶上及在血管系中之訊號強度 (濃度之函數關係）。圖中示出在注入標靶對比劑之後立即並無顯著濃度的對比劑出現在固定標把血检上，經過一段時間後，在固定標靶上之標靶對比劑濃度才增加。此時間過程依據作用物滲透至固定標免之速率，及作用物對固定標挺之特異親和力而定。之後在固定標把上之標乾作用物濃度會減少。因此在固定標靶上之訊號強度上升，到達最高點，再下降。擷取固定標靶影像之較佳時間是當固定標把中之訊號強度接近其峰·時，且在其他周圍組織中之標把作用物減至最低時。在明白標靶對比劑同時存在於血液（血管系，如靜脈）及在固定標·把時。若在注射後立即擷取影像數據，則血液之訊號強度將比得上，或大於固定標靶之訊號強度。圖中證明在固定標靶顯著加強劑，血管系此訊號加強作用β此早先之數據組可生成血管描記圖-即血管系之成像。由於在此 _____ -62- _ 本紙張尺度適用中國國家標準(CNS) Α·4規格(210X 297公釐） 1221406 A7 B7 五、發明説明（59 ) 成像中之固定標乾可因較亮的血液周圍而受阻，因此單獨以此成像並非偵測固定標靶之最佳成像。若在血液中之訊號趨近基線水平時擷取第二組顯影數據，但此時在固定標乾之訊號強度仍高，如圖中所示，則固定標靶對血管系之對比十分高。第二顯影數據組即可成像出固定標靶。比較此二數據組，將可更加確定標乾及血管系間之相互關係。 :在使用血管作用物繼之標靶作用物後，分析血管系及固定標靶上之訊號強度圖2 B證明，當標靶對比劑在投予血管劑之後投予至病人，隨著時間在固定標靶及在血管系中可顯示出訊號強度 (濃度之函數關係）。圖中示出，標纪對比劑注入後立即地固定標靶（血栓）並無顯著的強度，此乃因標靶對比劑存在於固定標靶上，一段時間後標靶對比劑在固定標靶上之濃度才會增加。此時間依作用物穿透至固定標纪之速率及標把劑對固定標乾之特異親和力而定。此時間點之後，在固定標乾上之標fe作用物濃度會減少。因此，固定標把之訊號強度上升’到達最大值，再下降。顯影固定標把的較佳時間是當固定標乾中之訊號強度接近其高峰》，且由其他周園組織中標靶作用物之強度最低之時。貫際上’標乾對比劑同時存在於血管系（如靜脈）及固定標把上。-然而，由於投予低劑量之標靶對比劑，血液之訊號強度可能太低以致無法產生血管系清楚的成像。細胞外或血液匯集對比劑可在標靶對比劑之前，同時或之後投予至病人’以提供血管系之成像。在所示出之圖中，血管作 -63- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)Isaiah 1221406 A7 _____B7 V. Description of the invention (58) Angle = 27 °. At first, the blood signal seems brighter than the thrombus. With time, the blood signal gradually declines and the intensity of the thrombus signal continues. In this way, the thrombus becomes brighter than the blood. Early blood vessel data, combined with later data, showed that the thrombus was strengthened. The data indicated on the back are combined again and visualized using the Algotec Provision workstation to show the location of the enhanced blood clots in the vascular system, as described above. Example 3: Analyzing signal strength in a vascular system and using a target substance alone on a fixed target Figure 2A demonstrates that when a target contrast agent is used to develop a vascular system and a fixed target, 'on a fixed target relative to time And signal strength (as a function of concentration) in the vascular system. The figure shows that no significant concentration of contrast agent appeared on the fixed target blood test immediately after the target contrast agent was injected. After a period of time, the target contrast agent concentration on the fixed target increased. This time course depends on the rate of penetration of the target into the fixed target and the specific affinity of the target for the fixed target. After that, the concentration of the target substance on the fixed handle will decrease. Therefore, the signal strength on the fixed target increases, reaches the highest point, and then decreases. The best time to capture a fixed target image is when the signal intensity in the fixed target is close to its peak, and the target in other surrounding tissues minimizes the effect of the target. It is understood that the target contrast agent exists in the blood (vascular system, such as veins) and when the target is fixed. If image data is acquired immediately after injection, the signal strength of the blood will be comparable or greater than the signal strength of the fixed target. The figure demonstrates that when the target is significantly enhanced by the fixed target, the signal enhancement of the vascular system β. This previous data set can generate an angiogram-the imaging of the vascular system. Because here _____ -62- _ This paper size applies Chinese National Standard (CNS) A · 4 size (210X 297mm) 1221406 A7 B7 V. Description of the invention (59) The fixed standard in imaging can be brighter. It is blocked around the blood, so this imaging alone is not the best imaging for detecting fixed targets. If the second set of imaging data is acquired when the signal in the blood approaches the baseline level, but the signal intensity of the fixed target is still high at this time, as shown in the figure, the contrast of the fixed target to the vascular system is very high. The second development data set can form a fixed target. Comparing these two data sets will further determine the correlation between the standard and the vascular system. : After using the vascular agent followed by the target agent, analyze the signal strength on the vascular system and fixed target. Figure 2B proves that when the target contrast agent is administered to the patient after the vascular agent is administered, Fixed targets and signal strength (as a function of concentration) can be displayed in the vascular system. The figure shows that there is no significant strength in fixing the target (thrombus) immediately after the injection of the standard contrast agent. This is because the target contrast agent exists on the fixed target. After a period of time, the target contrast agent is on the fixed target. Concentration will increase. This time depends on the rate of penetration of the target to the fixed standard and the specific affinity of the target agent for the fixed standard. After this time point, the concentration of the target substance on the fixed standard stem will decrease. Therefore, the signal strength of the fixed indicator rises to a maximum value, and then decreases. The best time to develop a fixed marker is when the signal intensity in the fixed marker is close to its peak, and when the intensity of the target substance in other garden tissues is the lowest. On the whole, the 'standard dry contrast agent exists in both vascular systems (such as veins) and fixed handles. -However, due to the administration of low-dose target contrast agents, the signal strength of the blood may be too low to produce clear imaging of the blood vessels. Extracellular or blood pooled contrast agents can be administered to a patient ' before, simultaneously with, or after the target contrast agent to provide imaging of the vascular system. In the picture shown, the blood vessels are made -63- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)

裝訂Binding

1221406 A7 ______B7___五、發明説明（6〇 ) 用物在注入標靶對比劑之前投予。可擷取血管系影像，同時由於血管劑之存在可加強血管系之訊號強度。一旦血管作用物清除後，且血管系之訊號加強同時減低時，標靶作用物再注入以使固定標靶成像。宜例5.：組合數據組方法之具體實例現參見圖3，描述將相當於血管對比顯影之數據組與相當於標靶對比顯影之數據組組合之流程，以生成第三數據組。在流程中所指之數學符號如下： A :代表對比加強之血管系數據組 T :代表對比加強之固定標把數據組（如血栓）〇:輸出之數據組 α，石：數據組之標度係數，其組合以產生輸出數據組 Ο 〇 a : Α之子集，只包括對比有加強之血管系訊號。此子集可由任何欲求之處理後方法中決定。 t : Τ之子集，只包括對比有加強之固定標靶（如血栓）訊號。此子集可由任何欲求之處理後方法決定。 b : A或T之任一子集，由固定標靶或血管系任一者專一之結構組成。此子集可由任何欲求的處理後方法決定。 a，b，-t，A，T及Ο各組有相同的次元，即若必要時可如上述地***補及註明。在步驟30，子集a被產生，且在步驟31，子集t被產生。在步驟32，子集b被產生。接下來在步驟33，當第一及第 __-64-____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）1221406 A7 ______B7___ V. Description of the invention (60) The object is administered before the target contrast agent is injected. It can capture the image of vascular system. At the same time, the signal strength of vascular system can be enhanced due to the presence of vascular agents. Once the vascular effect is cleared and the signal of the blood vessel is strengthened and decreased at the same time, the target effect is re-injected to image the fixed target. Preferable case 5 .: Specific example of the method of combining data sets Now referring to FIG. 3, the process of combining a data set equivalent to vascular contrast development with a data set equivalent to target contrast development is described to generate a third data set. The mathematical symbols referred to in the process are as follows: A: stands for contrast-enhanced blood vessel data set T: stands for contrast-enhanced fixed target data set (such as thrombus) 〇: output data set α, stone: scale of data set Coefficients, which are combined to produce an output data set OOa: a subset of A, which includes only contrasted vascular signals. This subset can be determined by any desired post-processing method. t: a subset of T, including only contrast-enhanced fixed targets (such as thrombus) signals. This subset can be determined by any desired post-processing method. b: any subset of A or T, consisting of either a fixed target or a structure unique to the vascular system. This subset can be determined by any desired post-processing method. The groups a, b, -t, A, T, and 0 have the same dimensions, that is, if necessary, can be interpolated and noted as described above. In step 30, a subset a is generated, and in step 31, a subset t is generated. At step 32, a subset b is generated. Next in step 33, when the first and the first __- 64 -____ this paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝訂等Binding, etc.

1221406 A7 _— B7 五、發明~6〇 '~" " 二數據組為獨立的MRI掃描結果時，再依下式產生輸出之數據組〇 : ⑴ 0= α Α+ /3 Τ (Π) 〇i = max( a A, /S T) 在這些方私式中’ α及沒為預定的可變加重係數。在等式I中，輸出數據組Ο由一般正式的算術產生。在等中，輸出組0由只取空間中最高1之各座標值產生，即，，最強"之訊號。在等式I中，α及/3之數值較好在ι>α，y5>〇範圍中，且α +沒=1為較好。此加重係數之範圍，可使輸出數據組與貢獻數據組有大約相同之強度幅度，且只用以確保輸出之數據組不會有任何顯著的表現誤差。需要更多詳盡的偵測以確保輸出正確，使數據組可針對貯存之可變型式可利用最大的代表性範圍。典型而言，在MR成像中，DICOM 數據組並不需此動態範圍操作，因此對大多例子而言， α，点係數應已足夠。在等式11中，α及/9之數值較妤均相同於1，在此例中所生成之數據組0在單一成像中於對比加強之固定標靶（如血检）及對比加強之血管系（如血液匯集）有單一的代表。α及沒可操作使Α及Τ數據組間之基礎強度差異可互補，以確保最佳之操·作生成可代表血管系（血液匯集）及固定標靶（血栓）之適當的數據組呈現結果。經由處理係演算法由來源數據組衍生而來之第一及第二數據組之一或二者後’再依以下等式產生輸出數據組〇 : ______ -65^_ f紙張尺度適财S S家標準(CNS) Α4規格(21G X 297公爱)~ " A7 B7 五、發明説明（62 ) (III) 0=αΑ 土 (IV) 0=aa+沒τ (V) 0= a a+ /5 t+ 7 t 和上述例子類似，在這些等式中，α ,沒及了為相對加重之係數。較佳之數值係在1>α，沒，r>〇之範圍内，且較好α+/ + Τ=1。於等式（111)中，將加重之固定標靶（如血栓）遮掩之數據組，加至含有血管系資料之數據組，當適當地履行時可生成其中固定標靶（如血栓）及血管系之數據組可互相區別，且周圍的組織也可經由強度差異而區別。等式（IV)和等式（III)顯著地相似，除了血管資料整體加至含有固定標靶（如血栓）之數據組中。等式（V)代表由原先顯影區二個片段組份來之輸出數據之生成。三種組份各自適當地加重可產生三種組份之強度差異有最大區別性之輸出數據組。宜Jli:利用標靶之MRI作用物，繼以血管MRI作用物於活體内偵測固定標靶 2.5公斤重之雌性紐西蘭白兔，以氣胺酮（5〇毫克/公斤）’艾西丙畊（2.5毫克/公斤）及若龐（5毫克/公斤）之摻和液麻醉，再以戊巴比妥鈉（約35毫克/公斤，依所需）維持。將靜脈内導管（24克）放入耳靜脈及耳動脈内。分出頸靜脈及頸動脈r。取18號針放血管上，以3-0縫線縫合定位可在頸動脈處造成狹窄。之後取出針，以顯微血管夾在狹窜處遠端切出5毫米動脈段片。動脈再沿5毫米段壓碎二次。鬆開近處血管夾，令血液流至段片内約3秒。再夾上夾子，動 -66- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)1221406 A7 _— B7 V. Invention ~ 6〇 '~ " " When the second data set is an independent MRI scan result, the output data set is generated according to the following formula: 0: ⑴ 0 = α Α + / 3 Τ (Π ) 〇i = max (a A, / ST) In these formulas, 'α and the variable weighting coefficient are not predetermined. In Equation I, the output data set 0 is generated by general formal arithmetic. In waiting, output group 0 is generated by taking only the highest coordinate values in space, that is, the strongest signal. In Equation I, the values of α and / 3 are preferably in the range of ι > α, y5 >, and α + not = 1 is better. The range of this emphasis coefficient can make the output data set and the contribution data set have approximately the same magnitude of intensity, and is only used to ensure that the output data set does not have any significant performance error. More detailed detection is required to ensure correct output so that the data set can use the most representative range for the stored variant. Typically, in MR imaging, the DICOM data set does not require this dynamic range operation, so for most examples, α, the point coefficient should be sufficient. In Equation 11, the values of α and / 9 are the same as 妤 compared to 妤. In this example, the data set 0 generated in a single image is a contrast-enhanced fixed target (such as a blood test) and a contrast-enhanced blood vessel. Departments (such as blood pools) have a single representative. Alpha and inoperability allow complementary base strength differences between the A and T data sets to ensure optimal operation. Generate appropriate data sets that represent blood vessels (blood pools) and fixed targets (thrombus) to present results. . One or both of the first and second data sets derived from the source data set through the processing algorithm are used to generate an output data set according to the following equation: ______ -65 ^ _ f Standard (CNS) Α4 specification (21G X 297 public love) ~ " A7 B7 V. Description of invention (62) (III) 0 = αΑ 土 (IV) 0 = aa + 无 τ (V) 0 = a a + / 5 t + 7 t is similar to the above example. In these equations, α is less than the coefficient that is relatively heavier. The preferred value is in the range of 1 > α, no, r > 0, and the better α + / + T = 1. In equation (111), the data set masked by the weighted fixed target (such as a thrombus) is added to the data set containing the data of the vascular system, and when properly performed, the fixed target (such as a thrombus) and the blood vessel can be generated The data sets of the systems can be distinguished from each other, and the surrounding tissues can also be distinguished by the intensity difference. Equations (IV) and (III) are significantly similar, except that the vascular data is added in its entirety to a data set containing a fixed target, such as a thrombus. Equation (V) represents the generation of output data from the two fragment components of the original development area. Proper weighting of each of the three components can produce an output data set with the greatest difference in strength between the three components. Yi Jli: using target MRI effector, followed by vascular MRI effector to detect 2.5 kg female New Zealand white rabbit with fixed target in vivo, using ketamine (50 mg / kg) Cingeng (2.5 mg / kg) and Roppong (5 mg / kg) were anesthetized with a blend of sodium and pentobarbital sodium (approximately 35 mg / kg, as needed). An intravenous catheter (24 g) was placed in the ear vein and ear artery. Separate jugular vein and carotid artery r. A 18-gauge needle was placed on the blood vessel and sutured with 3-0 suture to cause stenosis at the carotid artery. After that, the needle was removed, and a 5 mm arterial segment was cut out at the distal end of the narrow channel with a microvascular clamp. The artery was crushed twice more along the 5 mm segment. Loosen the proximal vascular clamp to allow blood to flow into the segment for about 3 seconds. Clip again and move -66- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

裝 ijIj

1221406 A7 __ B7 五、發明説明（63 ) 脈再沿5毫米段壓碎二次。4分鐘後移開夾子，以顯微血管夾分出5毫米頸靜脈片。注入100微升3.7單位的凝血酶，〇·〇6 M CaCl2，及兔子全血之混合物可生成血栓。4分鐘後移開夾子。令血栓熟化約5 0分鐘。經由耳靜脈投予1 ·〇毫升之5 mM 結構I I I溶液（2微莫耳/公斤）。3 0分鐘後，動物置入 General Electric Signa LxC Vi 1.5 高壓掃描器内，利用 3D RF擾相梯度回波序列（SPGR)在以下參數下獲得第一組MRI 數據組及影像：TR = 39毫秒，ΤΕ=3·1毫秒，置換角度= 40。，視野=8公分，採集波寬=3 1.25 kHz。應用化學脂質飽和性，以及40毫米空間上方及下方之飽和帶。再3〇分鐘後，注入血管劑Gd-DTPA-BSA，3毫升的80 mM Gd溶液（80微莫耳Gd/公斤）。應用相同波序取得第二組mri數據組及影像。圖4A示出第一影像之最大強度投射（MIP )。在MIP上左手處有一區較亮處。圖4B示出注入血管劑Gd-DTPA-BSA 後立即取得第二影像之MIP。在此MIP中，血管如頸動脈及頊靜脈可容易地看出來。圖5是由圖4A及4B所代表數據組經由組合而生成之影像。由於此二影像有相同之解析度，且二種掃描有相同的解剖位置，則組合之影巷秧當於等式 U) ·· 〇=4·2Α + 0·8Τ。在圖5之組合影像中，很明顯的，由血检標乾作用物所加強之亮點區相當於動物之右頸動脈，可推知在動物之右頸動脈中有血栓。复土LL :利用標靶的MRI作用物單獨地於活體内偵測固定 _______：___ -67- 本紙張尺度相巾@ a家標準(CNS) Α4規格(2iGx 297公爱） !1221406 A7 __ B7 V. Description of the invention (63) The veins are crushed twice along the 5 mm section. After 4 minutes, the clip was removed and a 5 mm jugular vein slice was separated with a microvascular clip. Thrombus can be generated by injecting 100 μl of a mixture of 3.7 units of thrombin, 0.06 M CaCl2, and rabbit whole blood. After 4 minutes, remove the clip. Allow the thrombus to mature for about 50 minutes. 1.0 ml of a 5 mM structure I I I solution (2 micromolar / kg) was administered via the ear vein. After 30 minutes, the animals were placed in a General Electric Signa LxC Vi 1.5 high-voltage scanner, and the first set of MRI data sets and images were obtained using the 3D RF spoiled gradient echo sequence (SPGR) under the following parameters: TR = 39 ms, Τ = 3.1 milliseconds, permutation angle = 40. , Field of view = 8 cm, acquisition width = 3 1.25 kHz. Apply chemical lipid saturation and saturation bands above and below the 40 mm space. After another 30 minutes, the vascular agent Gd-DTPA-BSA, 3 ml of 80 mM Gd solution (80 micromolar Gd / kg) was injected. Apply the same wave sequence to obtain the second mri data set and image. FIG. 4A illustrates the maximum intensity projection (MIP) of the first image. There is a brighter area on the left hand side of the MIP. FIG. 4B shows the MIP of the second image obtained immediately after the injection of the vascular agent Gd-DTPA-BSA. In this MIP, blood vessels such as the carotid artery and the iliac vein can be easily seen. Fig. 5 is an image generated by combining the data groups represented by Figs. 4A and 4B. Since the two images have the same resolution, and the two scans have the same anatomical position, the combined shadow lane seedlings should be equal to the equation U) ·· 〇 = 4 · 2Α + 0 · 8Τ. In the combined image of FIG. 5, it is obvious that the highlight area enhanced by the blood test target is equivalent to the right carotid artery of the animal, and it can be inferred that there is a thrombus in the right carotid artery of the animal. Futu LL: Use the target's MRI effector to detect and fix it in vivo separately. _______: ___ -67- This paper size photo towel @ a 家标准 (CNS) Α4 size (2iGx 297 public love)!

裝訂Binding

攀 1221406Climb 1221406

標靶 3」公斤雌性·㈣蘭白兔以氣_(5〇毫克/公斤），艾西丙和.5毫克/公斤）及若龐（5毫克/公斤）之摻和液麻醉，再 =戊巴比妥納（約35毫克/公斤，依所需）維持。將靜脈内導 “24克)放入耳靜脈及耳動脈内。分出頸靜脈及頸動脈。取18號針放血管上’以3_G縫線縫合定位，可在頸動脈處，成狹f。之後取出針，以顯微血管爽在狹窄處遠端切出$ 毫米動脈段片。動脈再沿5毫米段壓碎二次。鬆開近處血管夾，令血液流至段片内約3秒。再夾上夾子，動脈再沿5毫米段壓碎二次。4分鐘後移開夾子，以顯微血管夾分出5毫米頸靜脈片。注入100微升3.7單位的凝血酶，〇〇6 M 及兔子全血之混合物可生成血栓。4分鐘後移開夾子。令血栓熟化45分鐘。動物置General Electric Signa LxCVi 1.5问壓掃描器内’並利用3D RF擾相梯度回波序列（spGR) 在以下參數下顯影：TR = 39毫秒，ΤΕ = 3·1毫秒，置換角度 =40度’視野=8公分，影像擷取之波宽=31·25 kHz。應用化學脂質飽和作用，以及4〇毫米空間上方及下方飽和帶。在注射前一次掃描後，1·5毫升的4.2 mM標靶對比劑溶液（2 微莫耳/公斤，結構I)經由耳靜脈投予，並重覆影像序列以得第一組MRI數據。令血中濃度下降歷3 5分鐘後，動物利用相同波存再次顯影以得第二組MRI數據。圖6A示出第一 MRI數據組之最大強度投射（MIP)。此為血管之加強，且吾等可鑑定出頸動脈及頸靜脈。圖6B是第二MRI數據組之MIP，在此吾等不再看見血管，但在成像中 -6β - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1221406 A7 B7 五、發明説明（ 65 ) 由標把對比劑可看出在上中區有一個較亮區域。圖7是由第一及第二MRI數據組1 : 1組合而成之成像（即等式（1): 0 = 0·5Α + 0.5Τ)(如，分別為圖6A及6B成像之實例），其中很明顯的在圖6 Β中觀察到之較亮區域相當於動物右頸動脈中之固定標靶，推知此中在動物之右頸動脈中有血栓。實例8 •注入標乾MRI對比劑後掏取之血管及固定標把 MR影像 3 ·0公斤重之雌性紐西蘭白兔，以***（5 〇毫克/公斤），艾西丙畊（2.5毫克/公斤）及若龐（5毫克/公斤）之摻和液麻醉’再以戊巴比妥鈉（約3 5毫克/公斤，依所需）維持。靜脈内導管（24克）放入耳靜脈及耳動脈内。分出頸靜脈及頸動脈。取1 8號針放血管上，以3 - 〇缝線縫合定位，可在頸動脈處造成狹窄。之後取出針，以顯微血管夾在狹窄處遠端切出5毫米動脈段片。動脈再沿5亳米段壓碎二次。鬆開近處血管夾，令血液流至段片内約3秒。再夾上夾子，動脈再沿5毫米段壓碎二次。4分鐘後移開夾子，以顯微血管夾分出5毫米頸靜脈片。注入10〇微升3 7單位的凝血酶，〇·〇6 M CaCla，及兔子全血之混合物可生成血栓^ 4分鐘後移開爽子。々血检熟化約40分鐘。動物置Generai Electric Signa LxC Vi 高壓掃描器内，並利用3 D RF擾相梯度回波序列 (SPGR)在以下參數下顯影·· TR = 39毫秒，ΤΕ = 3·1毫秒，置換角度=40度，視野=8公分，影像擷取波寬=31·25 kHz °應用化學脂質飽和作用及4〇亳米空間上方及下方之Target 3 "kg females · Cymbidium white rabbits are anesthetized with a mixture of Qi _ (50 mg / kg), Isopropyl and .5 mg / kg) and Ruo Pang (5 mg / kg) Barbitone (about 35 mg / kg, as needed) is maintained. Put the intravenous guide "24g" into the ear vein and ear artery. Separate the jugular vein and carotid artery. Take an 18-gauge needle and place it on the blood vessel with 3_G suture. It can be narrowed at the carotid artery. Then remove the needle, and cut out the $ mm arterial segment at the distal end of the stenosis with the microvessel. The artery is crushed twice along the 5mm segment. Loosen the proximal vascular clamp to allow blood to flow into the segment for about 3 seconds. .Clamp again, the artery is crushed twice along the 5mm section. After 4 minutes, remove the clip and use the microvascular clip to separate a 5mm jugular vein slice. Inject 100 microliters of 3.7 units of thrombin, 〇06 A mixture of M and rabbit whole blood can generate a thrombus. Remove the clip after 4 minutes. Allow the thrombus to mature for 45 minutes. The animal is placed in a General Electric Signa LxCVi 1.5 pressure scanner and 3D RF spoiled gradient echo sequence (spGR) Developed under the following parameters: TR = 39 milliseconds, TE = 3.1 milliseconds, displacement angle = 40 degrees, field of view = 8 cm, wave width of image capture = 31 · 25 kHz. Application of chemical lipid saturation, and 4 o Saturated bands above and below the millimeter space. After a scan before injection, 1.5 ml 4.2 mM target contrast solution (2 μmol / kg, structure I) was administered via the ear vein, and the image sequence was repeated to obtain the first set of MRI data. After the blood concentration was reduced for 35 minutes, the animals used the same The wave memory was re-developed to obtain the second set of MRI data. Figure 6A shows the maximum intensity projection (MIP) of the first MRI data set. This is the enhancement of blood vessels, and we can identify the carotid artery and jugular vein. Figure 6B is The MIP of the second MRI data set, here we no longer see blood vessels, but in the imaging -6β-This paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 mm) 1221406 A7 B7 V. Description of the invention ( 65) It can be seen from the standard contrast agent that there is a brighter area in the upper and middle area. Figure 7 is an imaging composed of the first and second MRI data sets 1: 1 (that is, equation (1): 0 = 0.5A + 0.5T) (for example, the imaging examples of Figs. 6A and 6B, respectively), in which the brighter area observed in Fig. 6B is equivalent to the fixed target in the right carotid artery of the animal. There is a thrombus in the right carotid artery of the animal. Example 8 • Vessel and solids removed after injection of standard MRI contrast agent Calibrate a female New Zealand white rabbit weighing 3.0 kg in MR images with a blend of ketamine (50 mg / kg), isoprotin (2.5 mg / kg), and rapon (5 mg / kg) Liquid anesthesia 'is then maintained with pentobarbital sodium (approximately 35 mg / kg, as needed). An intravenous catheter (24 g) is placed in the ear vein and ear artery. The jugular vein and carotid artery are separated. Take 1 An 8-gauge needle was placed on the blood vessel and sutured with a 3-0 suture to create a narrowing at the carotid artery. Then the needle was removed and a 5 mm arterial segment was cut out at the distal end of the stenosis with a microvascular clip. The artery was crushed twice more along the 5mm section. Loosen the proximal vascular clamp to allow blood to flow into the segment for about 3 seconds. The clamp is clamped again, and the vein is crushed twice along the 5 mm segment. After 4 minutes, the clip was removed and a 5 mm jugular vein slice was separated with a microvascular clip. Inject 100 μl of 37 units of thrombin, 0.06 M CaCla, and a mixture of rabbit whole blood to form a thrombus ^ 4 minutes later, remove Shuangzi. 々 Blood test is about 40 minutes. The animals were placed in a Generai Electric Signa LxC Vi high-voltage scanner and developed using the 3D RF spoiler gradient echo sequence (SPGR) under the following parameters: · TR = 39 ms, TE = 3.1 ms, displacement angle = 40 degrees , Field of view = 8 cm, image capture wave width = 31 · 25 kHz ° applying chemical lipid saturation and 40 m above and below the space

裝訂線Gutter

1221406 A7 ___ B7 五、發明説明（~~^7) ~~ "" 飽和帶。在一次掃描後，標靶對比劑（（丨0微莫耳/公斤）， 4.0毫升的7.6 mM結構23之溶液，如u s.臨時案"以肽為基礎之多元標靶對比劑，，所示，其為Zhang et al·，，於2001年 7 月 30 日所公告，Ser. No· 60/308,721 及Zhang et al·，之，，以肽為基礎之多元標靶對比劑，與其同時公告，系列號為_) 經由耳靜脈投予。成像序列在下8 〇分鐘内重覆。在選出之軸切片上針對血栓及正常頸靜脈，進行重點區域（RC)I)分析。在注射前，血栓及血液在MR影像中有同等強度。在標靶對比劑注射後擷取之第一成像顯示出和注射前影像比較下，血液加強4.4倍。和注射前影像比較下血栓也被加強。注射後的第二次掃描證明，和血液比較下血栓加強多2·2 倍。於研究期間血栓保持較血液為明亮（約3倍亮度）。總而 T之，標靶對比劑注入後之第一影像（血管系MRI影像）示出血管較明亮。隨著時間接下來之影像（固定的MRI影像）證明血液訊號減低，且固定標靶（如血栓）由於與血液比較下有較強之訊號，因此似乎較亮些。兔:注入標靶MRI對比劑後擷取固定標靶M R影像，繼以投予血管MRI對比劑並擷取血管μ R影像 3·1公斤雌性紐西蘭白兔以氣胺酮（5〇亳克/公斤），艾西丙畊（2.5孑克/公斤）及若龐（5毫克/公斤）之摻和液麻醉，再以戊巴比妥鈉（約35毫克/公斤，依所需）維持。將靜脈内導管（24克）放入耳靜脈及耳動脈内。分出頸靜脈及頸動脈。取18號針放血管上’以3-0缝線縫合定位，可在頸動脈處 -70, 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) —— ---- 1221406 A7 B7 五、發明説明（π ) 造成狹窄。之後取出針，以顯微血管夾在狹窄處遠端切出5 宅米動脈段片。動脈再沿5亳米段壓碎二次。鬆開近處血管夾，令血液流至段片内約3秒。再夾上夾子，動脈再沿5毫米段壓碎二次。4分鐘後移開夾子，以顯微血管夾分出5毫米頸靜脈片。注入1〇〇微升3 7單位的凝血酶，〇〇6 M CaCl2 及兔子全血之混合物可生成血栓。4分鐘後移開夾子。々血栓热化4 5分鐘。動物置Generai Electric Signa LxCVi 1·5高壓掃描器内，並利用3E) RF擾相梯度回波序列（SPGR) 在以下參數下顯影：T R = 3 9毫秒，τ e = 3.1毫秒，置換角度 =40度’視野=8公分，影像擷取之波寬=31 25 kHz。應用化學脂質飽和作用以及40毫米空間上方及下方飽和帶。在注入標乾MRI對比劑前的一次掃描後，1.5毫升的4.2 mM結構I溶液（見上）（2微莫耳/公斤）經由耳靜脈投予❶在下go分鐘時重覆顯影波序。在8 0分鐘後，注入血液匯集血管MRI 對比劑Gd-DTPA-BSA，3毫升80 mM Gd溶液（80微莫耳 Gd/公斤）。以相同的波序來擷取額外的顯影。在所選定之軸片上，針對血栓及正常頸靜脈進行重點區域（r〇I)分析。在注入標靶對比劑前，血栓及血液為同等強度。注射後擷取之第一影像示出血栓凝塊有顯著之加強（如一個亮點），而血液為略加強，其快速減少。和血液比較下，血栓亮度高2 —3倍。而注入血液匯集劑後，血液及血栓之訊號強度均劇烈地增加，提供血管系詳盡之光景。比較及組合二個影像可對固定標靶（血栓）及其所在提供詳盡之分析。實例1 0 :投予細胞外血管MRI對比劑後取得血管MR影 -71 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱)1221406 A7 ___ B7 V. Description of the invention (~~ ^ 7) ~~ " " Saturation zone. After a scan, the target contrast agent ((0 μmol / kg), 4.0 ml of a 7.6 mM structure 23 solution, such as USP provisional case " peptide-based multiple target contrast agent, As shown, it is Zhang et al., Published on July 30, 2001, Ser. No. 60 / 308,721 and Zhang et al., Of which, peptide-based multi-target contrast agents, meanwhile, Announcement, serial number is _) administered via ear vein. The imaging sequence was repeated within the next 80 minutes. A selected area of the axis was analyzed for thrombus and normal jugular vein (RC) I). Before the injection, the thrombus and blood had the same intensity in the MR image. The first image taken after the target contrast injection showed a 4.4-fold increase in blood compared to the pre-injection image. The thrombus was also enhanced compared to the pre-injection image. The second scan after the injection proved that the thrombus was strengthened 2 · 2 times compared to the blood. The thrombus remained brighter (about 3 times brighter) than the blood during the study. In summary, the first image (vascular MRI image) after the target contrast agent injection showed that the blood vessels were brighter. Over time, the images (fixed MRI images) proved that the blood signal was reduced, and fixed targets (such as blood clots) seemed brighter because they had stronger signals compared to blood. Rabbit: After injecting the target MRI contrast agent, acquire a fixed target MR image, then administer the vascular MRI contrast agent and capture the blood vessel μR image. 3.1 kg of female New Zealand white rabbits were treated with ketamine (50%) G / kg), anesthesia (2.5 g / kg) and Roppong (5 mg / kg) anesthetized with a blend, and then maintained with sodium pentobarbital (about 35 mg / kg, as needed) . An intravenous catheter (24 g) was placed in the ear vein and ear artery. Separate jugular vein and carotid artery. Take a 18-gauge needle and place it on a blood vessel with 3-0 suture suture, which can be -70 at the carotid artery. This paper size applies the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) ---- ---- 1221406 A7 B7 5. Description of the invention (π) causes narrowing. After that, the needle was taken out, and a 5-meter arterial segment was cut out at the distal end of the stenosis with a microvascular clip. The artery was crushed twice more along the 5mm section. Loosen the proximal vascular clamp to allow blood to flow into the segment for about 3 seconds. The clamp is clamped again, and the artery is crushed twice along the 5 mm segment. After 4 minutes, the clip was removed and a 5 mm jugular vein slice was separated with a microvascular clip. Inject 100 microliters of 37 units of thrombin, a mixture of 006 M CaCl2 and rabbit whole blood to form a thrombus. Remove the clip after 4 minutes. 々 The thrombus was heated for 4 5 minutes. Animals were placed in a Generai Electric Signa LxCVi 1.5 high-voltage scanner and developed using 3E) RF spoiled gradient echo sequence (SPGR) under the following parameters: TR = 39 ms, τ e = 3.1 ms, displacement angle = 40 Degree 'field of view = 8 cm, wave width of image capture = 31 25 kHz. Applications Chemical lipid saturation and saturation bands above and below 40 mm space. After a scan prior to the injection of the standard MRI contrast agent, 1.5 ml of a 4.2 mM structure I solution (see above) (2 μmol / kg) was administered via the ear vein to repeat the developmental wave sequence at the next go minute. After 80 minutes, blood was injected to pool the vascular MRI contrast agent Gd-DTPA-BSA, 3 ml of 80 mM Gd solution (80 micromolar Gd / kg). Capture additional developments in the same wave sequence. On selected axis films, a focal area (rOI) analysis was performed for thrombus and normal jugular vein. Before the target contrast agent is injected, the thrombus and blood are of equal strength. The first image acquired after the injection shows that the thrombus has a significant enhancement (such as a bright spot), while the blood is slightly stronger, which decreases rapidly. Compared with blood, the thrombus is 2-3 times brighter. After the blood pooling agent is injected, the signal strength of blood and thrombus increases sharply, providing a detailed view of the blood vessel system. Comparing and combining the two images provides a detailed analysis of the fixed target (thrombosis) and its location. Example 10: Obtain vascular MR images after administration of extracellular vascular MRI contrast agent -71-This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X 297 public love)

裝訂Binding

線 1221406 A7 B7 五、發明説明（68 ) 像，繼之投予標靶MRI對比劑及取得固定MR影像 600克天竺鼠（Hartley雄性）以***（5 0毫克/公斤），艾西丙，井（2.5毫克/公斤）及若龐（5毫克/公斤）之摻和液麻醉，再以戊巴比妥鈉（約35毫克/公斤，依所需）維持。在喉部切開，並分出一條頸靜脈。以血管夾分出1公分之頸靜脈段片。由動物中新鮮抽出之血液（50微升）混合以人類凝血酶 (50微升，4單位），並注入靜脈已夾住之段片中。在注入後4分鐘，移開夾子且令血栓熟化30分鐘。動物置 General Electric Signa LxCVi 1 ·5 高壓掃描器内，並利用3 D RF擾相梯度回波序列（SPGR)在以下參數下顯影：TR = 22毫秒，ΤΕ = 3·1毫秒，置換角度=40度，視野=8 公分，影像擴取波寬=31.25 kHz。在一次掃描後，細胞外血管MRI對比劑，GdDTPA(Magnevist®)，100微莫耳/公斤經由導管注入頸動脈内。在下3 0分鐘顯影波序5次，以擷取血管MRI數據組。3 0分鐘後，注入5微莫耳/公斤血栓標靶MRI對比劑（結構3 2，如U · S ·臨時案"以肽為基礎之多元標靶對比劑”，Zhang et al·，，公告於2001年7月30日，Ser. No· 60/308,721及"以肽-為基礎之多元標靶對比劑"，Line 1221406 A7 B7 V. Description of the invention (68) image, followed by the administration of the target MRI contrast agent and obtaining a fixed MR image 600 grams of guinea pigs (Hartley male) with ketamine (50 mg / kg), Isopropyl, well ( 2.5 mg / kg) and Ropon (5 mg / kg) in an anesthetized solution, and then maintained with pentobarbital sodium (about 35 mg / kg, as needed). An incision was made in the throat and a jugular vein was divided. A 1 cm jugular vein segment was divided by a blood vessel clip. Freshly drawn blood (50 microliters) from animals is mixed with human thrombin (50 microliters, 4 units) and injected into a segment of the vein that has been clamped. Four minutes after injection, the clip was removed and the thrombus was allowed to mature for 30 minutes. The animals were placed in a General Electric Signa LxCVi 1 · 5 high-voltage scanner and developed using the 3 D RF spoiler gradient echo sequence (SPGR) under the following parameters: TR = 22 ms, TE = 3.1 ms, displacement angle = 40 Degrees, field of view = 8 cm, image extraction width = 31.25 kHz. After one scan, an extracellular MRI contrast agent, GdDTPA (Magnevist®), 100 μmol / kg was injected into the carotid artery via a catheter. The imaging sequence was developed 5 times in the next 30 minutes to acquire a vascular MRI data set. After 30 minutes, inject 5 micromolar / kg thrombus target MRI contrast agent (Structure 32, such as U.S. Provisional Case " Peptide-based Multiple Target Contrast Agents, '' Zhang et al. ,, Announced on July 30, 2001, Ser. No. 60 / 308,721 and " Peptide-based Multiple Target Contrast ",

Zhang et al.,，與之同時公告，U.S·系列號_) 〇在下一 8 0分鐘採用相同的波序以擷取標靶]viRI數據組。在所選定之軸切片-上針對血栓及正常頸靜脈進行重點區域（ROI)分析。在血管M R顯影中，血管系有所加強（4倍），但血栓無可觀察之加強。在固定MR顯影中和血液比較下血栓似乎較 _-72-_____ 本紙張尺度逋用中國國家標準(CNS) A4規格(210X 297公釐） 1221406 A7 B7 五、發明説明（69 ) 亮，且此亮的顯影隨時間可慢慢褪色至標靶對比劑注射後 8 0分鐘。本發明許多具體實例已有所描述。然而，應了解只要不偏離本發明之精神及範圍此中可有許多的變化。因此，其他具體實例均在以下申請專利範圍之範疇之内。 -73- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐）Zhang et al., And announced at the same time, U.S. serial number _) 〇 In the next 80 minutes, the same wave sequence is used to capture the target] viRI data set. A focal area (ROI) analysis of the thrombus and normal jugular vein was performed on the selected axis slice. In the MR imaging of the blood vessels, the vascular line was strengthened (4-fold), but the thrombus was not observed to be strengthened. Compared with blood in fixed MR imaging, the thrombus seems to be more than _-72 -_____ This paper size uses the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1221406 A7 B7 5. The invention description (69) is brighter, and this Bright development can fade over time to 80 minutes after target contrast injection. Many specific examples of the invention have been described. However, it should be understood that many changes can be made therein without departing from the spirit and scope of the invention. Therefore, other specific examples are within the scope of the following patent applications. -73- This paper size applies to China National Standard (CNS) Α4 (210 X 297 mm)

Claims

1221406 月 5 年案(93 請本申換利替專圍 I範 9利 93專 11請 ?1申 ο文I 第中> ABC D 1¾氛修補六、申請專利範圍 1· 一種用於哺乳動物中血管系内固定標靶磁共振顯影（mri) 之診斷組合物，其含有標靶MRI對比劑，其中標靶mri 對比劑對固定標靶有特異的親和力，且標靶的mri對比劑進一步可提供哺乳動物固定標靶及血管系對比加強作用；其中含有血管系之影像之第一 MRI數據組係經擷取’及第二MRI數據組係在可適當地提供固定標靶（若存在下）在和背景血液及組織加強作用比較下 '可觀察之對比加強水平之時擴取。 2·根據申請專利範圍第1項之診斷組合物，其中第一及第二 MRI數據組係經比較以決定血管系内固定標靶之存在，限制條件為由第二MRI數據組示出固定標靶之存在。 3.根據申請專利範圍第2項之診斷組合物，其中藉由組合第一及第二MRI數據組來比較第一及第二MRI數據組以生成第三MRI數據組，第三MRI數據組包括固定標靶及血管系之影像，且第三數據組可示出固定標靶（若存在時）在血管系内之所在。 4·根據申凊專利範圍第3項之診斷組合物，其中第三Mpj數據組係在成像裝置上呈現，以示出固定標靶（若存在時）在血管系内之位置。 5·根據申請專利範圍第3項之診斷組合物，其中第三MRI數據組進一步可示出血管系内固定標靶之大小。 6·根據申請專利範圍第3項之診斷組合物，其中第一及第二 MRI數據組係藉互相在空間上註明加以組合。 7·根據申請專利範圍第3項之診斷組合物，其中第一及第二本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)1221406 May 5th case (93, please apply for the benefit of the replacement of I, 9, 93, 11, 11? 1 application, the first part of the text > ABC D 1¾ atmosphere repair 6, the scope of the patent application1. One for mammals The diagnostic composition of the magnetic resonance imaging (MR) of the fixed target in the middle blood vessel system contains the target MRI contrast agent, wherein the target mri contrast agent has specific affinity for the fixed target, and the target mri contrast agent can further Provides mammalian fixed targets and contrast enhancement of blood vessels; the first MRI data set containing images of blood vessels is captured and the second MRI data set is used to provide fixed targets (if any) where appropriate Expanded at the level of 'observable contrast enhancement' compared with background blood and tissue enhancement. 2. Diagnostic composition according to item 1 of the scope of patent application, where the first and second MRI data sets are compared to determine The limitation of the existence of fixed targets in the vascular system is that the presence of fixed targets is shown by the second MRI data set. 3. The diagnostic composition according to item 2 of the scope of patent application, wherein the first and second MRI are combined Data set Compare the first and second MRI data sets to generate a third MRI data set. The third MRI data set includes images of the fixed target and the vascular system, and the third data set can show the fixed target (if present) in Where it is inside the blood vessel. 4. The diagnostic composition according to item 3 of the patent application, wherein the third Mpj data set is presented on the imaging device to show that the fixed target (if present) is within the blood vessel. Location. 5. The diagnostic composition according to item 3 of the patent application, wherein the third MRI data set can further show the size of the fixed target in the blood vessel system. 6. The diagnostic composition according to item 3 of the patent application, where The first and second MRI data sets are combined by spatially indicating each other. 7. The diagnostic composition according to item 3 of the scope of the patent application, in which the first and second paper sizes apply the Chinese National Standard (CNS) A4 specification (210X 297 mm)

申請專利範圍數據係藉由將第一或第二mri數據組任一者空間解軒户又插補來組合，使得第一及第二MRI數據組有同等之二間解析度。〈2 8·根據申請專利範圍第1項之診斷組合物，其中診斷組人物包含一足以使投藥後之血中T】值少於5〇〇毫秒之劑量的標靶MRI對比劑。、 9.根據申請專利範圍第丨項之診斷組合物，其中診斷組合物包含一足以造成在投藥後血中τ i值少於3〇〇毫秒之劑量的標靶MRI對比劑。 β 1〇·根據申請專利範圍第9項之診斷組合物，其中診斷組合物包含一足以造成在投藥後血中τ丨值少於175毫秒之劑量的標靶MRI對比劑。 a根據申請專利範圍第}項之診斷組合物，其中標靶mri對比劑進一步對存在於哺乳動物血管系内之非固定生物組份呈現特異的親和力。 12.根據申請專利範圍第丨丨項之診斷組合物，其中存在於哺乳動物血管系内之非固定生物組份係選自由人類血清白蛋白’血纖維蛋白原，α -酸性醣蛋白，球蛋白，及脂蛋白所組成之群。 13·根據申請專利範圍第1 2項之診斷組合物，其中存在於哺乳動物血管系内之非固定生物組份是人類血清白蛋白。 14.根據申請專利範圍第i項之診斷組合物，其中在血管系内足固定標靶係選自由組織，生物結構，細胞，細胞表面’及生物聚合物所組成之群。The scope of the patent application data is combined by spatially interpreting either the first or the second mri data set and then interpolating, so that the first and second MRI data sets have the same two resolutions. <28. The diagnostic composition according to item 1 of the scope of the patent application, wherein the person in the diagnostic group includes a target MRI contrast agent at a dose sufficient to cause a T] value in the blood after administration to be less than 500 milliseconds. 9. The diagnostic composition according to item 1 of the scope of the patent application, wherein the diagnostic composition comprises a target MRI contrast agent in a dose sufficient to cause a τ i value in the blood after administration of less than 300 milliseconds. β 1 0. The diagnostic composition according to item 9 of the scope of patent application, wherein the diagnostic composition comprises a target MRI contrast agent in a dose sufficient to cause a τ 丨 value in the blood after administration to be less than 175 milliseconds. a The diagnostic composition according to item} of the patent application scope, wherein the target mri contrast agent further exhibits a specific affinity for non-fixed biological components existing in the mammalian vascular system. 12. The diagnostic composition according to the scope of application patent item 丨丨, wherein the non-fixed biological component present in the mammalian vascular system is selected from the group consisting of human serum albumin 'fibrinogen, α-acid glycoprotein, globulin , And a group of lipoproteins. 13. The diagnostic composition according to item 12 of the scope of the patent application, wherein the non-fixed biological component present in the mammalian vascular system is human serum albumin. 14. The diagnostic composition according to item i of the patent application, wherein the fixed target in the blood vessel line is selected from the group consisting of tissue, biological structure, cell, cell surface 'and biopolymer.

D8 '中請專利範圍 15. 根據申請專利範圍第1 4項之診斷組合物，其中的生物結構係選自由血栓，動脈粥樣硬化斑，動脈粥樣硬化傷害，腫瘤，及血栓插栓所組成之群。 16. 根據申請專利範圍第1 4項之診斷組合物，其中的生物聚合物係選自由脂質，脂蛋白，蛋白質，多肽，及多醣所組成之群。 17·根據申凊專利範圍第1 6項之診斷組合物，其中的生物聚合？物是選自由血纖維蛋白及膠原蛋白所組成之群之蛋白質。二 18.根據申請專利範圍第1項之診斷組合物，其包括足以造成固定標靶之T !值少於500毫秒之劑量的標靶MRI對比劑。 19·根據申請專利範圍第1 8項之診斷組合物，其包括足以造成固定標靶之T i值少於300毫秒之劑量的標靶MRI對比劑。 2〇·根據申請專利範圍第i 9項之診斷組合物，其包括足以造成固定標靶之T丨值少於100毫秒之劑量的標靶MRI對比劑。 21·根據申請專利範圍第i項之診斷組合物，其包括約〇〇〇1 至約5 00微莫耳/公斤之標靶mrj對比劑。 22.根據申請專利範圍第21項之診斷組合物，其包括約0.001 至約50微莫耳/公斤之標靶MRI對比劑。 23·根據申請專利範圍第22項之診斷組合物，其包括約0.001 至約5微莫耳/公斤之標靶mri對比劑。 24·根據申請專利範圍第1項之診斷組合物，其中標靶MRI對比划對固定標革巴有特異的親和力，以解離常數表示是少 -3-D8 'patent claim 15. The diagnostic composition according to item 14 of the patent application scope, wherein the biological structure is selected from the group consisting of thrombus, atherosclerotic plaque, atherosclerotic injury, tumor, and thromboembolism Group. 16. The diagnostic composition according to item 14 of the patent application, wherein the biopolymer is selected from the group consisting of lipids, lipoproteins, proteins, peptides, and polysaccharides. 17. The diagnostic composition according to item 16 of the patent application scope, where is the biopolymer? The substance is a protein selected from the group consisting of fibrin and collagen. 18. A diagnostic composition according to item 1 of the scope of patent application, which comprises a target MRI contrast agent in a dose sufficient to cause a fixed target T! Value of less than 500 milliseconds. 19. A diagnostic composition according to item 18 of the scope of patent application, which comprises a target MRI contrast agent in a dose sufficient to produce a fixed target with a T i value of less than 300 milliseconds. 20. The diagnostic composition according to item i 9 of the scope of patent application, which comprises a target MRI contrast agent sufficient to produce a fixed target with a T value less than 100 milliseconds. 21. The diagnostic composition according to item i of the patent application scope, which comprises a target mrj contrast agent of about 0.001 to about 5,000 micromoles / kg. 22. The diagnostic composition according to item 21 of the patent application scope, comprising a target MRI contrast agent of about 0.001 to about 50 micromoles / kg. 23. The diagnostic composition according to item 22 of the scope of patent application, which comprises a target mri contrast agent of about 0.001 to about 5 micromoles / kg. 24. The diagnostic composition according to item 1 of the scope of patent application, in which the target MRI comparison has a specific affinity for a fixed target, which is less as a dissociation constant.

^1406^ 1406

25. 根據申請專利範圍第“項之診斷 ?:r固定標免具有特異的親“以= 疋少於5 。 26. 根據申請專利範圍第25項之診斷組合物，對tr固定標财特異的親和力，⑽離常數表示，少於0.5 。 27. =:專利範圍第1項之診斷組合物1中標娜對比劑係選自由下列所組成之群：結構I :25. According to the scope of the patent application, "Diagnosis?: R fixed standard exemption has a specific affinity" to = 疋 less than 5. 26. According to the diagnostic composition of the scope of application for patent No. 25, the specific affinity for the fixed fixed asset of tr is expressed by the deviation constant, which is less than 0.5. 27. =: The standard composition of the diagnostic composition 1 in the patent scope item 1 is selected from the group consisting of: Structure I:

-4- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1221406 8 8 8 8 A BCD 六、申請專利範圍結構II : 〇-4- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1221406 8 8 8 8 A BCD VI. Patent application scope Structure II: 〇

-5- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 06 4 1A 2 12 8 8 8 8 A B c D 申請專利範圍結構IV : rU^N-| HO1¾¾ OH ,NH2 HN HO、-5- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 06 4 1A 2 12 8 8 8 8 AB c D Patent application scope structure IV: rU ^ N- | HO1¾¾ OH, NH2 HN HO ,

Λ HOΛ HO

NH u -y r vpt,<kpN^cr° OH 結構V :NH u -y r vpt, < kpN ^ cr ° OH structure V:

-6 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1221406 六、申請專利範圍結構VI : 8 8 8 8 A B c D 〇-6-This paper size applies Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1221406 6. Scope of patent application Structure VI: 8 8 8 8 A B c D 〇

00

ο--ο--

HOYHOY

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 06 4 2 12 8 8 8 8 A B c D 六、申請專利範圍結構VIII :This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 06 4 2 12 8 8 8 8 A B c D 6. Scope of patent application Structure VIII:

及結構IX : 0And structure IX: 0

28·根據申請專利範圍第1項之診斷組合物，其中第二MRI數據組是利用擾相梯度回波序列擷取。 -8- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)28. The diagnostic composition according to item 1 of the scope of patent application, wherein the second MRI data set is acquired using a spoiled gradient echo sequence. -8- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

六、申請專利範圍 29.根據中請專利範圍第1項之診斷组合物，其中第—及第 MRI數據組係在單一 MRI段落中擷取。其中單一之 30·根據申請專利範圍第2 9項之診斷組合物 MRI段落係持續不到6小時。其中單一々 31·根據申請專利範圍第3 〇項之診斷組合物 MRI段落係持續不到4小時。其中單一 ^ 32·根據申請專利範圍第3丨項之診斷組合物 MRI段落係持續不到2小時。其中單一二 33·根據申請專利範圍第3 2項之診斷組合物 MRI段落係持續不到1小時。 34. -種決定哺乳動物血管系内固定餘存在與否之診斷套組，其包含用於製備第一及第二診斷組合物之一標靶 MRI對比劑及一血管題對_，其中標㈣比劑對固足標靶具有特異的親和力，且標靶對比劑可提供固定標 I&對比加強作用；血管對比劑可提供哺乳動物血管系對比加強作用，其中包括有血管系之影像之血管數據組係經擷取，且標靶MRI數據組亦經擷取，標靶數據組擷取的時間是適於提供固定標靶（若存在時）相較於背景血液及組織加強作用有可觀察之對比加強水平之時。 35. 根據申μ專利範圍第3 4項之診斷套組，其中血管及標乾 MRI數據組係經比較以決定血管系内固定標靶之存在，限制條件為標靶MRI數據組示出固定標靶之存在。 36·根據申請專利範圍第3 5項之診斷套組，其中血管及標靶 MRI數據組係經組合以產生第三mri數據組，第三數據 ___ -9- 本紙張尺度適用中國國家標準(CNS)八4規$_1〇><297公釐) 12214066. Scope of patent application 29. The diagnostic composition according to item 1 of the patent application, wherein the first and second MRI data sets are acquired in a single MRI segment. The single 30. The diagnostic composition according to item 29 of the patent application. The MRI paragraph lasted less than 6 hours. Among them, 31. The diagnostic composition according to item 30 of the patent application scope. The MRI segment lasts less than 4 hours. The single ^ 32. The diagnostic composition according to item 3 of the patent application scope. The MRI segment lasted less than 2 hours. The single two 33. The diagnostic composition according to item 32 of the scope of patent application. The MRI segment lasts less than 1 hour. 34. A diagnostic kit for determining the presence or absence of internal fixation in mammalian vascular systems, comprising a target MRI contrast agent and a vascular question pair _ for preparing the first and second diagnostic compositions, where The specific agent has specific affinity for the fixed foot target, and the target contrast agent can provide a fixed standard I & contrast enhancement effect; the vascular contrast agent can provide a mammalian vascular system contrast enhancement effect, including vascular data of the image of the vascular system The group is captured and the target MRI data set is also captured. The target data set is captured at a time suitable to provide a fixed target (if present) compared to the background blood and tissue strengthening effect. When contrast levels are enhanced. 35. According to the diagnostic kit of item 34 of the patent application scope, the vascular and standard MRI data sets are compared to determine the existence of fixed targets in the vascular system. The limitation is that the target MRI data sets show fixed targets. The existence of the target. 36. According to the diagnostic set of the 35th scope of the patent application, the vascular and target MRI data sets are combined to generate a third mri data set, the third data ___ -9- This paper scale applies Chinese national standards ( CNS) 8 rules $ _1〇 > < 297 mm) 1221406

A8 B8A8 B8

v 組包括固足標把及血管系之影像，且第三數據組示出血管系内固定標靶（若存在時）之所在。 37_根據申請專利範圍第36項之診斷套組，其中第三刪數據、、且係在成像裝置上呈現，以示出血管系内固定標革巴（若存在時）之所在。 38.根據申請專利範圍第36項之診斷套組，數據組進-步示出血管系内固定標乾之大小中。弟一順^ 39·根據申請專利範圍第34項之診斷套組，其中標乾對比劑：裝之投用係在血管對比劑之前，且其中血管MRI數據組之擷取是在標靶MRI數據組之前。 40.根據申請專利範圍第34項之診斷套組，其中的標乾對比劑及血管對比劑係同時投用，且其中標乾腦數據組之擴取係在血管MRI數據組之前。 41·根據申請專利範圍第34項之診斷套組，其中的標乾對比劑及血管對比劑互相投用的時間在2小時之内。Group v includes images of fixed foot handles and blood vessels, and the third data group shows the location of fixed targets in the blood vessels (if present). 37_ The diagnostic kit according to item 36 of the scope of the patent application, in which the third data is deleted and presented on the imaging device to show the location of the internal fixation standard of the blood vessel (if present). 38. According to the diagnostic kit of item 36 of the scope of patent application, the data set further shows the size of the fixed standard in the vascular system. Di Yishun ^ 39. The diagnostic kit according to item 34 of the scope of patent application, in which the standard contrast agent is filled: the application is placed before the vascular contrast agent, and the vascular MRI data set is captured in the target MRI data Before the group. 40. The diagnostic kit according to item 34 of the application, wherein the standard contrast agent and the vascular contrast agent are administered simultaneously, and the expansion of the standard brain data set is before the vascular MRI data set. 41. According to the diagnostic kit according to item 34 of the scope of patent application, the standard contrast agent and vascular contrast agent are administered within 2 hours of each other.

42·根據申請專利範圍第41項之診斷套組，其中的標靶對比劑及血管對比劑互相投用的時間在3〇分鐘之内。 43·根據申請專利範圍第42項之診斷套組，其中的標靶對比劑及血管對比劑互相投用的時間在1 5分鐘之内。 44.根據申請專利範圍第34項之診斷套組，其中標靶數據組及血管MRI數據組係在單一 MRI段落中擷取。 45_根據申請專利範圍第3 6項之診斷套組，其中標乾及血管 MRI數據組係藉互相在空間上予以註明加以組合。 46.根據申請專利範圍第3 6項之診斷套組，其中標乾及血管 -10-42. According to the diagnostic kit according to item 41 of the scope of patent application, the target contrast agent and the vascular contrast agent are administered within 30 minutes of each other. 43. According to the diagnostic kit according to item 42 of the scope of the patent application, the target contrast agent and the vascular contrast agent are administered to each other within 15 minutes. 44. The diagnostic kit according to item 34 of the patent application, wherein the target data set and the vascular MRI data set are acquired in a single MRI segment. 45_ The diagnostic kit according to item 36 of the scope of patent application, in which the standard trunk and vascular MRI data sets are spatially marked and combined with each other. 46. The diagnostic kit according to item 36 of the scope of patent application, in which the standard stem and blood vessels -10-

申清專利範Apply for patent

MRI數據組係藉將血管或標靶MRI數據組任一者之空間解析插補加以組合，如此血管及標㈣RI數據組有相合的空間解析度。 37 47.根據中請專利範圍第34項之診斷套組，其中第二診斷組 ^物包含足以造成在投藥後血中丁丨值少於3〇〇毫秒之劑量的血管MRI對比劑。 ^ 48·根據申請專利範圍第47項之診斷套組，纟中第二診斷組合物包含足以造成在投藥後血中τ丨值少於175毫秒之劑量的血管MRI對比劑。 θ 49. 根據申請專利範圍第48項之診斷套組，其中第二診斷組合物包含足以造成在投藥後血中τ丨值少於〗〇〇毫秒之劑量的血管MRI對比劑。产 50. 根據申請專利範圍第3 4項之診斷套組，其中的血管％幻對比劑是細胞外MRI對比劑，其係選自由下列所組成之群： C〇2 广 Gd3+ ) C〇2 C〇2 (Gd-DTPA)， -11 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1221406 A8 B8 C8 D8 申請專利範圍 co2· -C02 .N N、Gd3+ ：N N〆 O2C_ c〇2' (Gd-DOTA), C02· CH3NHOC—v /~\ /—CONHCH3 N N N Γ Gd3+ 1 C02· C02· (Gd-DTPA-BMA), •〇2〇 C02*Gd3+ :N N〆 .CH3 OH CO, (Gd-HP-D03A), co2· CH3OCH2CH2NHOC- ' /~\\/~\ /—CONHCH2CH20CH3 N N N < _ Gd3+ ) _ C〇2 C〇2 (gadoversetamide)，及The MRI data set is a combination of spatially resolved interpolation of either the blood vessel or the target MRI data set, so that the blood vessel and the target RI data set have a consistent spatial resolution. 37 47. The diagnostic kit according to item 34 of the patent application, wherein the second diagnostic kit contains a vascular MRI contrast agent in a dose sufficient to cause a blood value of less than 300 milliseconds after administration. ^ 48. According to the diagnostic kit of item 47 of the scope of the patent application, the second diagnostic composition in the middle contains a vascular MRI contrast agent in a dose sufficient to cause a τ 丨 value in the blood to be less than 175 milliseconds after administration. θ 49. The diagnostic kit according to item 48 of the scope of patent application, wherein the second diagnostic composition comprises a vascular MRI contrast agent in a dose sufficient to cause a τ 丨 value in the blood after administration to be less than 00 milliseconds. 50. The diagnostic kit according to item 34 of the scope of the patent application, wherein the vascular% magic contrast agent is an extracellular MRI contrast agent, which is selected from the group consisting of: C〇2 广 Gd3 +) C〇2 C 〇2 (Gd-DTPA), -11-This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1221406 A8 B8 C8 D8 Patent application scope co2 · -C02 .NN, Gd3 +: NN〆O2C_ c 〇2 '(Gd-DOTA), C02 · CH3NHOC—v / ~ \ / —CONHCH3 NNN Γ Gd3 + 1 C02 · C02 · (Gd-DTPA-BMA), • 〇2〇C02 * Gd3 +: NN〆.CH3 OH CO , (Gd-HP-D03A), co2 · CH3OCH2CH2NHOC- '/ ~ \\ / ~ \ / —CONHCH2CH20CH3 NNN < _ Gd3 +) _ C〇2 C〇2 (gadoversetamide), and

(gadobutol). -12- 本紙張尺度適用中》國家標準(CNS) A4規格(210X 297公釐) 1221406 、申請專利範圍 51. 根據申請專利範圍第3 4項之診斷套組，其中的血管MRI 對比劑係選自由氧化鐵之超小粒子（USPIOs)及單晶體氧化鐵粒子（MIONs)所組成之群。 52. 根據申請專利範圍第3 4項之診斷套組，其中的血管MRI 對比劑是血液匯集對比劑。 53. 根據申請專利範圍第5 2項之診斷套組，其中的血管MRI 血液匯集對比劑係選自由下列所組成之群··(gadobutol). -12- Applicable to the standard of this paper "National Standard (CNS) A4 specification (210X 297 mm) 1221406, patent application scope 51. According to the diagnostic scope of the patent application scope item 34, among which vascular MRI The contrast agent is selected from the group consisting of ultra small particles of iron oxide (USPIOs) and single crystal iron oxide particles (MIONs). 52. The diagnostic kit according to item 34 of the application, wherein the vascular MRI contrast agent is a blood pooling contrast agent. 53. The diagnostic kit according to item 52 of the scope of patent application, wherein the vascular MRI blood pooling contrast agent is selected from the group consisting of:

C〇2 -co2· C〇2 (Gd-BOPTA), o-C〇2 -co2 C〇2 (Gd-BOPTA), o-

Gadomer-17, P760, C02· (Gd-EOB-DTPA), OH -〇：Gadomer-17, P760, C02 · (Gd-EOB-DTPA), OH -〇:

13-13-

(MP-2269), 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1221406 A B c D 申請專利範圍〇(MP-2269), this paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1221406 A B c D Patent application scope 〇

〇 (MS-325)，及〇 (MS-325), and

- C XOr *〇2〇^ Gd3+ 、C〇2 •02C〆 54. 根據申請專利範圍第3 4項之診斷套組，其中的血管MRI 對比劑進一步對存在於哺乳動物血管系内之非固定生物組份呈現特異的親和力。 55. 根據申請專利範圍第5 4項之診斷套組，其中在哺乳動物血管系内之非固定生物組份係選自由人類血清白蛋白，血纖維蛋白原，α -酸性糖蛋白，球蛋白，及脂蛋白所組成之群。 -14- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1221406 A8 B8 C8 D8 申請專利範圍地根據中請專利第55項之診斷套組，其中在哺乳動物血管系内之非固定生物組份是人類血清白蛋白。 57. 根據中請專利範圍第34項之診斷套組，其中在血管系内〈固定標靶係選自由組織’生物結構，細胞，細胞表面及生物聚合物所組成之群。 58. 根據中請專利範圍第57項之診斷套組，纟中的生物結構係選自由血栓，動脈粥樣硬化斑，動脈粥樣硬化傷害，腫瘤及血检插检所組成之群。说根據申請專利範圍第57項之診斷套組’其中的生物聚合物係選自由脂質，脂蛋白，蛋白質，多月太，及多酷所组成之群。 60·根據申請專利範圍第59項之診斷套組，其中的生物聚合物疋係選自由血纖維蛋白及膠原蛋白所組成之群之蛋白質。 61·根據申請專利範圍第34項之診斷套組，其中第一診斷組合物包含足以造成固定標靶之T i值少於5〇〇毫秒之劑量的標靶MRI對比劑。 62·根據中請專利範圍第6丨項之診斷套組，其中第一診斷組合物包含足以造成固定標靶之τ ι值少於3〇〇毫秒之劑量的標靶MRI對比劑。 63·根據申請專利範圍第6 2項之診斷套組，其中第一診斷組合物包含足以造成固定標靶之T i值少於1〇〇毫秒之劑量的標靶MRI對比劑。 64·根據申請專利範圍第3 4項之診斷套組，其中第一診斷組 L___ -15- 本紙張尺度仙中國时標準(CNS) A4規格(210 X 297公爱) 裝訂 # 1221406 A8 B8 C8 D8 六、申請專利範圍合物包含約0.001至約500微莫耳/公斤標靶MRI對比劑，且第一診斷組合物包含約〇·〇1至約3⑽微莫耳/公斤之血管MRI對比劑。 65.根據申請專利範圍第64項之診斷套組，其中第一診斷組口物包含約0.001至約50微莫耳/公斤之標靶對比劑，且第二診斷組合物包含約001至約30微莫耳/公斤之血管MRI對比劑。 66·根據中請專利範圍第65項之診斷套組，其中第_診斷组合=包含約0._至約5微莫耳/公斤之標㈣㈣比劑，且第二診斷组合物約〇〇1至約3微莫耳/公斤之血管 67.根據申請專利範圍第3 4項之診斷套比劑對固定標靶有特異的親和力，於 5 0 // Μ 〇組’其中標靶MRI對以解離常數表示係少訂-C XOr * 〇2〇 ^ Gd3 +, C〇2 • 02C〆54. According to the diagnostic kit of item 34 of the patent application scope, the vascular MRI contrast agent further targets non-fixed organisms existing in the mammalian vascular system. The components exhibit specific affinity. 55. The diagnostic kit according to item 54 of the scope of patent application, wherein the non-fixed biological component in the mammalian blood vessel line is selected from the group consisting of human serum albumin, fibrinogen, α-acid glycoprotein, globulin, And lipoprotein groups. -14- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1221406 A8 B8 C8 D8 The scope of patent application is based on the diagnostic kit of item 55 of the Chinese patent, which is in the mammalian vascular system The non-fixed biological component is human serum albumin. 57. The diagnostic kit according to item 34 of the patent application, wherein the fixed target system is selected from the group consisting of a tissue 'biological structure, a cell, a cell surface, and a biopolymer within a blood vessel system. 58. According to the diagnostic set of patent application No. 57, the biological structure in the urn is selected from the group consisting of thrombus, atherosclerotic plaque, atherosclerotic injury, tumor and blood test. It is said that according to the 57th diagnostic scope of the patent application ', the biopolymer is selected from the group consisting of lipids, lipoproteins, proteins, Tatsukita, and Doku. 60. The diagnostic kit according to item 59 of the application, wherein the biopolymer is a protein selected from the group consisting of fibrin and collagen. 61. The diagnostic kit according to item 34 of the application, wherein the first diagnostic composition comprises a target MRI contrast agent in a dose sufficient to cause a fixed target with a T i value of less than 500 milliseconds. 62. The diagnostic kit according to item 6 of the patent application, wherein the first diagnostic composition comprises a target MRI contrast agent at a dose sufficient to cause a fixed target with a τ ι value of less than 300 milliseconds. 63. The diagnostic kit according to item 62 of the scope of the patent application, wherein the first diagnostic composition comprises a target MRI contrast agent in a dose sufficient to cause a fixed target with a T i value of less than 100 milliseconds. 64 · According to the diagnostic kit of item 34 of the scope of patent application, the first diagnostic group is L___ -15- This paper size is China Standard (CNS) A4 specification (210 X 297 public love) Binding # 1221406 A8 B8 C8 D8 6. The scope of the patent application The composition includes a target MRI contrast agent of about 0.001 to about 500 micromoles / kg, and the first diagnostic composition contains a blood vessel MRI contrast agent of about 0.01 to about 3 micromoles / kg. 65. The diagnostic kit according to item 64 of the scope of patent application, wherein the mouthpiece of the first diagnosis group contains a target contrast agent of about 0.001 to about 50 micromoles / kg, and the second diagnosis composition contains about 001 to about 30 Micromolar / kg vascular MRI contrast agent. 66. The diagnostic kit according to item 65 of the patent application, wherein the _diagnostic combination = a standard ratio agent containing about 0. to about 5 micromoles / kg, and the second diagnostic composition is about 0.01 To about 3 micromoles per kilogram of blood vessels 67. According to the diagnostic kit of item 34 of the patent application scope, the specific binding agent has a specific affinity for the fixed target. In the 50 // M0 group, the target MRI pair is dissociated. Constant means less order

裝 68·根據申請專利範圍第6 7項之診斷套比劑對固定標靶具有特異的親和力少於5 。組’其中標靶MRI對 ’以解離常數表示係 69·根據申請專利範圍第6 8項之診斷套比劑對固定標靶有特異的親和力，於 0.5 // Μ 〇 '组’其中標靶MRI對以解離常數表示係少 # 其中標靶MRI對 70·根據申請專利範圍第3 4項之診斷套組比劑係選自由下列所組成之群：本紙張尺度適財S國冢料_)鐵格_χ297公爱)-------- 1221406 8 8 8 8 A B c D 々、申請專利範圍結構I : 〇68. The diagnostic kit according to item 67 of the scope of patent application has a specific affinity for fixed targets of less than 5. Group 'where the target MRI pair' is expressed by the dissociation constant 69. According to the diagnostic kit No. 68 of the application patent scope, the specific ratio of the specific target has a fixed affinity for the fixed target. In the 0.5 // Μ 〇 'group' where the target MRI is The number of dissociation constants is represented by ## Where the target MRI pair is 70. The diagnostic kit according to item 34 of the scope of patent application is selected from the group consisting of the following:格 _χ297 公爱) -------- 1221406 8 8 8 8 AB c D 々, patent application scope structure I: 〇

結構II :Structure II:

〇 -17- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 0642 12 8 8 8 8 A B c D 々、申請專利範圍結構III :〇 -17- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 0642 12 8 8 8 8 A B c D 々, patent application structure III:

-18- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1221406 8 8 8 8 A B c D 申請專利範圍結構V Λ-18- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1221406 8 8 8 8 A B c D Patent application scope Structure V Λ

ClCl

NHNH

恭Christine

結構VI :Structure VI:

-19- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） A8 B8 C8 D8-19- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) A8 B8 C8 D8

12214061221406

A B c D 第3 4項之診斷套組，其中標靶MRI數其中血管MRI對其中血管MRI對及結構IX :A B c D The diagnostic kit of item 34, in which the number of target MRIs are vascular MRI pairs among which vascular MRI pairs and structure IX:

71 ·根據申請專利範園據組係利用擾相梯度回波T列而擴取―。 72. 根據申請專利範圍第34項之診斷套組比劑係以快速濃注方式投用。 73. 根據申請專利範圍第3 4項之診斷套組比劑係以輸注方式投用，且輸注時間少於 74. 根據申請專利範圍第73項之診斷套組，其里少於1 0分鐘。飛]/王呷間 75·根據申請專利範圍第7 4項之診斷套組，少於3分鐘。于間 21 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）71 · According to the patent application Fan Yuan According to the system, the spoiled gradient echo T column is used to expand and obtain ―. 72. The diagnostic kit according to item 34 of the scope of the patent application is used as a rapid injection. 73. The diagnostic kit according to item 34 of the scope of the patent application The specific agent is administered by infusion and the infusion time is less than 74. The diagnostic kit according to item 73 of the patent scope is less than 10 minutes. Fly] / Wang Jianjian 75. According to the diagnostic kit of the scope of patent application No. 74, less than 3 minutes. Yu 21-This paper size applies to China National Standard (CNS) A4 (210X297 mm)

12214061221406

圖4AFigure 4A

圖4B _〇〇Figure 4B _〇〇